Combination of anti-lag-3 antibodies and anti-pd-1 antibodies to treat tumors

ABSTRACT

Provided are methods for clinical treatment of tumors (e.g., advanced solid tumors) using an anti-LAG-3 antibody in combination with an anti-PD-1 antibody.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/880,606, filed Sep. 20, 2013 and U.S. Provisional Application No.62/014,471, filed Jun. 19, 2014. The contents of any patents, patentapplications, and references cited throughout this specification arehereby incorporated by reference in their entireties.

BACKGROUND

Lymphocyte activation gene-3 (LAG-3; CD223) is a type I transmembraneprotein that is expressed on the cell surface of activated CD4⁺ and CD8⁺T cells and subsets of NK and dendritic cells (Triebel F, et al., J.Exp. Med. 1990; 171:1393-1405; Workman C T, et al., J. Immunol. 2009;182(4):1885-91). LAG-3 is closely related to CD4, which is a co-receptorfor T helper cell activation. Both molecules have 4 extracellularIg-like domains and require binding to their ligand, majorhistocompatibility complex (MHC) class II, for their functionalactivity. In contrast to CD4, LAG-3 is only expressed on the cellsurface of activated T cells and its cleavage from the cell surfaceterminates LAG-3 signaling. LAG-3 can also be found as a soluble proteinbut it does not bind to MHC class II and its function is unknown.

It has been reported that LAG-3 plays an important role in promotingregulatory T cell (Treg) activity and in negatively regulating T cellactivation and proliferation (Workman C J, et al., J. Immunol. 2005;174:688-695). Both natural and induced Treg express increased LAG-3,which is required for their maximal suppressive function (Camisaschi C,et al., J. Immunol. 2010; 184:6545-6551 and Huang C T, et al., Immunity.2004; 21:503-513). Furthermore, ectopic expression of LAG-3 on CD4⁺effector T cells reduced their proliferative capacity and conferred onthem regulatory potential against third party T cells (Huang C T, etal., Immunity. 2004; 21:503-513). Recent studies have also shown thathigh LAG-3 expression on exhausted lymphocytic choriomeningitis virus(LCMV)-specific CD8⁺ T cells contributes to their unresponsive state andlimits CD8⁺ T cell antitumor responses (Blackburn S D, et al., Nat.Immunol. 2009; 10:29-37 and Grosso J F, et al., J. Clin. Invest. 2007;117:3383-3392). In fact, LAG-3 maintained tolerance to self and tumorantigens via direct effects on CD8⁺ T cells in 2 murine models (Grosso JF, et al., J. Clin. Invest. 2007; 117:3383-3392).

Immune tolerance observed in the setting of tumor development and tumorrecurrence, however, seems to be mediated by the co-expression ofvarious T cell negative regulatory receptors, not solely from LAG-3.Data from chronic viral infection models (Blackburn S D, et al., Nat.Immunol. 2009; 10:29-37, Grosso J F, et al., J. Clin. Invest. 2007;117:3383-3392, and Lyford-Pike S, et al., Cancer Res. 2013;73(6):1733-41), knock-out mice (Woo S R, et al., Cancer Res. 2012;72:917-927; Okazaki T, et al., J. Exp Med. 2011; 208:395-407, andBettini M. et al., J. Immunol. 2011; 187:3493-3498), tumor recurrencemodels (Goding S R, et al., J. Immunol. 2013; 190(9):4899-4909) and, toa more limited extent, human cancer patients (Goding S R, et al., J.Immunol. 2013; 190(9):4899-4909, Matsuzaki J, et al., Proc. Natl. Acad.Sci., USA. 2010; 107:7875-7880, and Gandhi M K, et al., Blood. 2006;108:2280-2289) support a model wherein T cells that are continuouslyexposed to antigen become progressively inactivated through a processtermed “exhaustion.” Exhausted T cells are characterized by theexpression of T cell negative regulatory receptors, predominantlyCTLA-4, PD-1, and LAG-3, whose action is to limit the cell's ability toproliferate, produce cytokines, and kill target cells and/or to increaseTreg activity. However, the timing and sequence of expression of thesemolecules in the development and recurrence of tumors have not beenfully characterized.

Programmed Cell Death 1 (PD-1) is a cell surface signaling receptor thatplays a critical role in the regulation of T cell activation andtolerance (Keir M E, et al., Annu Rev Immunol 2008; 26:677-704). It is atype I transmembrane protein and together with BTLA, CTLA-4, ICOS andCD28, comprise the CD28 family of T cell co-stimulatory receptors. PD-1is primarily expressed on activated T cells, B cells, and myeloid cells(Dong H, et al., Nat Med. 1999; 5:1365-1369). It is also expressed onnatural killer (NK) cells (Terme M, et al., Cancer Res 2011;71:5393-5399). Binding of PD-1 by its ligands, PD-L1 and PD-L2, resultsin phosphorylation of the tyrosine residue in the proximal intracellularimmune receptor tyrosine inhibitory domain, followed by recruitment ofthe phosphatase SHP-2, eventually resulting in down-regulation of T cellactivation. One important role of PD-1 is to limit the activity of Tcells in peripheral tissues at the time of an inflammatory response toinfection, thus limiting the development of autoimmunity (Pardoll D M.,Nat Rev Cancer 2012; 12:252-264). Evidence of this negative regulatoryrole comes from the finding that PD-1-deficient mice develop lupus-likeautoimmune diseases including arthritis and nephritis, along withcardiomyopathy (Nishimura H, et al., Immunity, 1999; 11:141-151; andNishimura H, et al., Science, 2001; 291:319-322). In the tumor setting,the consequence is the development of immune resistance within the tumormicroenvironment. PD-1 is highly expressed on tumor-infiltratinglymphocytes, and its ligands are up-regulated on the cell surface ofmany different tumors (Dong H, et al., Nat Med 2002; 8:793-800).Multiple murine cancer models have demonstrated that binding of ligandto PD-1 results in immune evasion. In addition, blockade of thisinteraction results in anti-tumor activity (Topalian S L, et al. NEJM2012; 366(26):2443-2454; Hamid O, et al., NEJM 2013; 369:134-144).Moreover, it has been shown that inhibition of the PD-1/PD-L1interaction mediates potent antitumor activity in preclinical models(U.S. Pat. Nos. 8,008,449 and 7,943,743).

Patients with metastatic or refractory solid tumors have very poorprognosis (Rosenberg S A, et al., Cancer immunotherapy in Cancer:Principles & Practice of Oncology (Eds DeVita V T, Lawrence T S andRosenberg S A) 2011; 332-344 (Lippincott Williams & Wilkins,Philadelphia Pa.)). Despite advances in multimodal therapy, increases inoverall survival in this patient population have been limited.Accordingly, it is an object of the present invention to provideimproved methods for treating subjects with such tumors (e.g., advancedrefractory solid tumors).

SUMMARY

Provided herein are methods for treating tumors in a human patient,particularly solid tumors (e.g., advanced refractory solid tumors),comprising administering to the patient a combination of an anti-LAG-3antibody and an anti-PD-1 antibody, wherein the combination isadministered (or is for administration) according to a particularclinical dosage regimen (i.e., at a particular dose amount and accordingto a specific dosing schedule). In one embodiment, the human patientsuffers from melanoma, non-small cell lung cancer (NSCLC),virally-related cancer, head and neck cancer (HNC) or gastricadenocarcinoma.

An exemplary anti-LAG-3 antibody is BMS-986016 comprising heavy andlight chains comprising the sequences shown in SEQ ID NOs:1 and 2,respectively, or antigen binding fragments and variants thereof. Inother embodiments, the antibody comprises the heavy and light chaincomplementarity determining regions (CDRs) or variable regions (VRs) ofBMS-986016. Accordingly, in one embodiment, the antibody comprises CDR1,CDR2, and CDR3 domains of the heavy chain variable (VH) region ofBMS-986016 having the sequence shown in SEQ ID NO:3, and CDR1, CDR2 andCDR3 domains of the light chain variable (VL) region of BMS-986016having the sequence shown in SEQ ID NO:5. In another embodiment, theantibody comprises CDR1, CDR2 and CDR3 heavy chain sequences set forthin SEQ ID NOs:7, 8, and 9, respectively, and CDR1, CDR2 and CDR3 lightchain sequences as set forth in SEQ ID NOs:10, 11, and 12, respectively.In another embodiment, the antibody has VH and/or VL regions comprisingthe amino acid sequences set forth in SEQ ID NO:3 and/or SEQ ID NO:5,respectively. In another embodiment, the antibody comprises the VHand/or VL regions encoded by the nucleic acid sequences set forth in SEQID NO:4 and/or SEQ ID NO:6, respectively. In another embodiment, theantibody competes for binding with, and/or binds to the same epitope onLAG-3 as, the above-mentioned antibodies. In another embodiment, theantibody has at least about 90% variable region amino acid sequenceidentity with the above-mentioned antibodies (e.g., at least about 90%,95% or 99% variable region identity with SEQ ID NO:3 or SEQ ID NO:5).

An exemplary anti-PD-1 antibody is Nivolumab (also referred to as “5C4”in WO 2006/121168; and known as BMS-936558, MDX-1106 and ONO-4538)comprising heavy and light chains comprising the sequences shown in SEQID NOs:17 and 18, respectively, or antigen binding fragments andvariants thereof. In other embodiments, the antibody comprises the heavyand light chain CDRs or VRs of BMS-936558. Accordingly, in oneembodiment, the antibody comprises CDR1, CDR2, and CDR3 domains of theVH region of BMS-936558 having the sequence shown in SEQ ID NO:19, andCDR1, CDR2 and CDR3 domains of the VL region of BMS-936558 having thesequence shown in SEQ ID NO:21. In another embodiment, the antibodycomprises heavy chain CDR1, CDR2 and CDR3 domains comprising thesequences set forth in SEQ ID NOs:23, 24, and 25, respectively, andlight chain CDR1, CDR2 and CDR3 domains comprising the sequences setforth in SEQ ID NOs: 26, 27, and 28, respectively. In anotherembodiment, the antibody comprises VH and/or VL regions comprising theamino acid sequences set forth in SEQ ID NO: 19 and/or SEQ ID NO:21,respectively. In another embodiment, the antibody comprises the heavychain variable (VH) and/or light chain variable (VL) regions encoded bythe nucleic acid sequences set forth in SEQ ID NO:20 and/or SEQ IDNO:22, respectively. In another embodiment, the antibody competes forbinding with, and/or binds to the same epitope on PD-1 as, theabove-mentioned antibodies. In another embodiment, the antibody has atleast about 90% variable region amino acid sequence identity with theabove-mentioned antibodies (e.g., at least about 90%, 95% or 99%variable region identity with SEQ ID NO:19 or SEQ ID NO:21).

Accordingly, in one aspect, methods of treating solid tumors (e.g.,advanced refractory solid tumors) in a human patient are provided, themethods comprising administering to the patient, an effective amount ofeach of:

(a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of theheavy chain variable region having the sequence set forth in SEQ IDNO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable regionhaving the sequence set forth in SEQ ID NO:5,

(b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of theheavy chain variable region having the sequence set forth in SEQ IDNO:19, and CDR1, CDR2 and CDR3 domains of the light chain variableregion having the sequence set forth in SEQ ID NO:21,

wherein the method comprises at least one administration cycle, whereinthe cycle is a period of eight weeks, wherein for each of the at leastone cycles, four doses of the anti-LAG-3 antibody are administered at adose of 3, 20, 80, or 240 mg and four doses of the anti-PD-1 antibodyare administered at a dose of 80 or 240 mg. In another embodiment, fourdoses of the anti-LAG-3 antibody are administered at a dose of about0.03, 0.25, 1, or 3 mg/kg body weight and four doses of the anti-PD-1antibody are administered at a dose of 1 or 3 mg/kg body weight.

In one embodiment, the anti-LAG-3 antibody and anti-PD-1 antibody areadministered at the following doses:

(a) 3 mg anti-LAG-3 antibody and 80 mg of anti-PD-1 antibody;

(b) 3 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody;

(c) 20 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody;

(d) 80 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody; or

(e) 240 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody.

In another embodiment, the anti-LAG-3 antibody and anti-PD-1 antibodyare administered at the following doses:

(a) 0.03 mg/kg anti-LAG-3 antibody and 1 mg/kg of anti-PD-1 antibody;

(b) 0.03 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody;

(c) 0.25 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody;

(d) 1 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody; or

(e) 3 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody.

In one embodiment, the dose of the anti-LAG-3 and/or anti-PD-1 antibodyis calculated per mg/kg body weight. In another embodiment, the dose ofthe anti-LAG-3 and/or anti-PD-1 antibody is a flat-fixed dose. Inanother embodiment, an intermediate dose of LAG-3 and/or PD-1 is used.For example, LAG-3 could be administered at 0.4 mg/kg and PD-1 could beadministered at 90 mg/kg. In another embodiment, dosage regimens areadjusted to provide the optimum desired response (e.g., an effectiveresponse).

In another embodiment, the anti-PD-1 antibody is administered on Days 1,15, 29, and 43 of each cycle. In another embodiment, the anti-LAG-3antibody is administered on Days 1, 15, 29, and 43 of each cycle. Inanother embodiment, the anti-PD-1 antibody is administered prior toadministration of the anti-LAG-3 antibody. In another embodiment, theanti-PD-1 antibody is administered after administration of theanti-LAG-3 antibody. In another embodiment, the treatment consists of upto 12 cycles.

In one embodiment, the anti-PD-1 antibody and anti-LAG-3 antibody areadministered as a first (“front”) line of treatment (e.g., the initialor first treatment). In another embodiment, the anti-PD-1 antibody andanti-LAG-3 antibody are administered as a second line of treatment(e.g., after initial treatment with the same or a different therapeutic,including after relapse and/or where the first treatment has failed).The anti-LAG-3 and anti-PD-1 antibodies can be administered to a subjectby any suitable means. In one embodiment, the antibodies are formulatedfor intravenous administration. In another embodiment, the antibodiesare administered simultaneously (e.g., formulated together in a singleformulation or concurrently as separate formulations). Alternatively, inanother embodiment, the antibodies are administered sequentially (e.g.,as separate formulations). In another embodiment the anti-LAG-3 antibodyis administered within about 30 minutes (e.g., within about 29, 28, 27,26, 25, 24, 23, 22, 21, 20, or less minutes) prior to administration ofthe anti-PD-1 antibody.

The efficacy of the treatment methods provided herein can be assessedusing any suitable means. In one embodiment, the treatment produces atleast one therapeutic effect selected from the group consisting ofreduction in size of a tumor, reduction in number of metastatic lesionsover time, complete response, partial response, and stable disease.

Also provided are kits that include a pharmaceutical compositioncontaining an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1antibody, such as BMS-936558, and a pharmaceutically-acceptable carrier,in a therapeutically effective amount adapted for use in the methodsdescribed herein. In one embodiment, the kit comprises:

(a) a dose of an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3domains of the heavy chain variable region having the sequence set forthin SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chainvariable region having the sequence set forth in SEQ ID NO:5;

(b) a dose of an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3domains of the heavy chain variable region having the sequence set forthin SEQ ID NO:19, and CDR1, CDR2 and CDR3 domains of the light chainvariable region having the sequence set forth in SEQ ID NO:21; and

(c) instructions for using the anti-LAG-3 antibody and anti-PD-1antibody in a method of the invention.

In another aspect, an anti-LAG-3 antibody is provided, the anti-LAG-3antibody comprising CDR1, CDR2 and CDR3 domains of the heavy chainvariable region having the sequence set forth in SEQ ID NO:3, and CDR1,CDR2 and CDR3 domains of the light chain variable region having thesequence set forth in SEQ ID NO:5, for co-administration with ananti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of the heavychain variable region having the sequence set forth in SEQ ID NO:19, andCDR1, CDR2 and CDR3 domains of the light chain variable region havingthe sequence set forth in SEQ ID NO:21, in at least one cycle, whereinfor each cycle four doses of the anti-LAG-3 antibody are administered ata dose of 3, 20, 80, or 240 mg and four doses of the anti-PD-1 antibodyare administered at a dose of 80 or 240 mg. In another embodiment, fourdoses of the anti-LAG-3 antibody are administered at a dose of 0.03,0.25, 1, or 3 mg/kg body weight and four doses of the anti-PD-1 antibodyare administered at a dose of 1 or 3 mg/kg body weight.

In another aspect of the invention, the anti-PD-1 antibody in any of theaforementioned embodiments is replaced by, or combined with, ananti-PD-L1 or anti-PD-L2 antibody. Accordingly, the invention alsofeatures methods, compositions and kits for treating tumors in humanpatients using the above-described clinically effective dosages of ananti-LAG-3 antibody combined with the above-described clinicallyeffective dosages of an anti-PD-1 antibody, wherein the dosage of thePD-1 antibody is replaced with the same dosage of an anti-PD-L1 oranti-PD-L2 antibody.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows inhibition of tumor growth in vivo using a combinationtreatment of an anti-LAG-3 antibody and an anti-PD-1 antibody in amurine tumor model.

FIGS. 2A and 2B are schematics illustrating the parts of a phase Iclinical trial.

FIG. 3 is a schematic illustrating the Screening, Treatment, ClinicalFollow-up, and Survival Follow-up phases of the clinical trial.

DETAILED DESCRIPTION I. Definitions

As used herein, the term “subject” or “patient” is a human cancerpatient (e.g., a patient having an advanced solid tumor, such as anadvanced refractory solid tumor).

As used herein, “effective treatment” refers to treatment producing abeneficial effect, e.g., amelioration of at least one symptom of adisease or disorder. A beneficial effect can take the form of animprovement over baseline, i.e., an improvement over a measurement orobservation made prior to initiation of therapy according to the method.A beneficial effect can also take the form of arresting, slowing,retarding, or stabilizing of a deleterious progression of a marker ofsolid tumor. Effective treatment may refer to alleviation of at leastone symptom of a solid tumor. Such effective treatment may, e.g., reducepatient pain, reduce the size and/or number of lesions, may reduce orprevent metastasis of a tumor, and/or may slow tumor growth.

The term “effective amount” refers to an amount of an agent thatprovides the desired biological, therapeutic, and/or prophylacticresult. That result can be reduction, amelioration, palliation,lessening, delaying, and/or alleviation of one or more of the signs,symptoms, or causes of a disease, or any other desired alteration of abiological system. In reference to solid tumors, an effective amountcomprises an amount sufficient to cause a tumor to shrink and/or todecrease the growth rate of the tumor (such as to suppress tumor growth)or to prevent or delay other unwanted cell proliferation. In someembodiments, an effective amount is an amount sufficient to delay tumordevelopment. In some embodiments, an effective amount is an amountsufficient to prevent or delay tumor recurrence. An effective amount canbe administered in one or more administrations. The effective amount ofthe drug or composition may: (i) reduce the number of cancer cells; (ii)reduce tumor size; (iii) inhibit, retard, slow to some extent and maystop cancer cell infiltration into peripheral organs; (iv) inhibit(i.e., slow to some extent and may stop tumor metastasis; (v) inhibittumor growth; (vi) prevent or delay occurrence and/or recurrence oftumor; and/or (vii) relieve to some extent one or more of the symptomsassociated with the cancer. In one example, an “effective amount” is theamount of anti-LAG-3 antibody and the amount of anti-PD-1 antibody, incombination, clinically proven to affect a significant decrease incancer or slowing of progression of cancer, such as an advanced solidtumor. As used herein, the terms “fixed dose”, “flat dose” and“flat-fixed dose” are used interchangeably and refer to a dose that isadministered to a patient without regard for the weight or body surfacearea (BSA) of the patient. The fixed or flat dose is therefore notprovided as a mg/kg dose, but rather as an absolute amount of the agent(e.g., the anti-LAG-3 antibody and/or anti-PD-1 antibody).

As used herein, a “body surface area (BSA)-based dose” refers to a dose(e.g., of the anti-LAG-3 antibody and/or anti-PD-1 antibody) that isadjusted to the body-surface area (BSA) of the individual patient. ABSA-based dose may be provided as mg/kg body weight. Variouscalculations have been published to arrive at the BSA without directmeasurement, the most widely used of which is the Du Bois formula (seeDu Bois D, Du Bois E F (June 1916) Archives of Internal Medicine 17 (6):863-71; and Verbraecken, J. et al. (April 2006). Metabolism—Clinical andExperimental 55 (4): 515-24). Other exemplary BSA formulas include theMosteller formula (Mosteller R D. N Engl J Med., 1987; 317:1098), theHaycock formula (Haycock G B, et al., J Pediatr 1978, 93:62-66), theGehan and George formula (Gehan E A, George S L, Cancer Chemother Rep1970, 54:225-235), the Boyd formula (Current, J D (1998), The InternetJournal of Anesthesiology 2 (2); and Boyd, Edith (1935), University ofMinnesota. The Institute of Child Welfare, Monograph Series, No. x.London: Oxford University Press), the Fujimoto formula (Fujimoto S, etal., Nippon Eiseigaku Zasshi 1968; 5:443-50), the Takahira formula(Fujimoto S, et al., Nippon Eiseigaku Zasshi 1968; 5:443-50), and theSchlich formula (Schlich E, et al., Ernährungs Umschau 2010;57:178-183).

The term “antibody” describes polypeptides comprising at least oneantibody-derived antigen binding site (e.g., VH/VL region or Fv, orCDR). Antibodies include known forms of antibodies. For example, theantibody can be a human antibody, a humanized antibody, a bispecificantibody, or a chimeric antibody. The antibody also can be a Fab, Fab′2,ScFv, SMIP, Affibody®, nanobody, or a domain antibody. The antibody alsocan be of any of the following isotypes: IgG1, IgG2, IgG3, IgG4, IgM,IgA1, IgA2, IgAsec, IgD, and IgE. The antibody may be a naturallyoccurring antibody or may be an antibody that has been altered (e.g., bymutation, deletion, substitution, conjugation to a non-antibody moiety).For example, an antibody may include one or more variant amino acids(compared to a naturally occurring antibody) which changes a property(e.g., a functional property) of the antibody. For example, numeroussuch alterations are known in the art which affect, e.g., half-life,effector function, and/or immune responses to the antibody in a patient.The term antibody also includes artificial polypeptide constructs whichcomprise at least one antibody-derived antigen binding site.

The term “LAG-3” refers to Lymphocyte Activation Gene-3. The term“LAG-3” includes variants, isoforms, homologs, orthologs and paralogs.For example, antibodies specific for a human LAG-3 protein may, incertain cases, cross-react with a LAG-3 protein from a species otherthan human. In other embodiments, the antibodies specific for a humanLAG-3 protein may be completely specific for the human LAG-3 protein andmay not exhibit species or other types of cross-reactivity, or maycross-react with LAG-3 from certain other species, but not all otherspecies (e.g., cross-react with monkey LAG-3 but not mouse LAG-3). Theterm “human LAG-3” refers to human sequence LAG-3, such as the completeamino acid sequence of human LAG-3 having Genbank Accession No.NP_002277 (SEQ ID NO:13). The term “mouse LAG-3” refers to mousesequence LAG-3, such as the complete amino acid sequence of mouse LAG-3having Genbank Accession No. NP_032505. LAG-3 is also known in the artas, for example, CD223. The human LAG-3 sequence may differ from humanLAG-3 of Genbank Accession No. NP_002277 by having, e.g., conservedmutations or mutations in non-conserved regions and the LAG-3 hassubstantially the same biological function as the human LAG-3 of GenbankAccession No. NP_002277. For example, a biological function of humanLAG-3 is having an epitope in the extracellular domain of LAG-3 that isspecifically bound by an antibody of the instant disclosure or abiological function of human LAG-3 is binding to MHC Class II molecules.

The term “monkey LAG-3” is intended to encompass LAG-3 proteinsexpressed by Old World and New World monkeys, including but not limitedto cynomolgus monkey LAG-3 and rhesus monkey LAG-3. A representativeamino acid sequence for monkey LAG-3 is the rhesus monkey LAG-3 aminoacid sequence which is also deposited as Genbank Accession No.XM_001108923. Another representative amino acid sequence for monkeyLAG-3 is the alternative rhesus monkey sequence of clone pa23-5 asdescribed in US 2011/0150892 A1. This alternative rhesus sequenceexhibits a single amino acid difference, at position 419, as compared tothe Genbank-deposited sequence.

A particular human LAG-3 sequence will generally be at least 90%identical in amino acid sequence to human LAG-3 of Genbank Accession No.NP_002277 and contains amino acid residues that identify the amino acidsequence as being human when compared to LAG-3 amino acid sequences ofother species (e.g., murine). In certain cases, a human LAG-3 can be atleast 95%, or even at least 96%, 97%, 98%, or 99% identical in aminoacid sequence to LAG-3 of Genbank Accession No. NP_002277. In certainembodiments, a human LAG-3 sequence will display no more than 10 aminoacid differences from the LAG-3 sequence of Genbank Accession No.NP_002277. In certain embodiments, the human LAG-3 can display no morethan 5, or even no more than 4, 3, 2, or 1 amino acid difference fromthe LAG-3 sequence of Genbank Accession No. NP_002277. Percent identitycan be determined as described herein.

As used herein, the terms “Programmed Death 1,” “Programmed Cell Death1,” “Protein PD-1,” “PD-1,” PD1,” “PDCD1,” “hPD-1” and “hPD-I” are usedinterchangeably, and include variants, isoforms, species homologs ofhuman PD-1, and analogs having at least one common epitope with PD-1.The complete PD-1 sequence can be found under GenBank Accession No.U64863 (SEQ ID NO:29).

The protein Programmed Death 1 (PD-1) is an inhibitory member of theCD28 family of receptors, that also includes CD28, CTLA-4, ICOS andBTLA. PD-1 is expressed on activated B cells, T cells, and myeloid cells(Agata et al., supra; Okazaki et al. (2002) Curr. Opin. Immunol. 14:391779-82; Bennett et al. (2003) J Immunol 170:711-8). The initialmembers of the family, CD28 and ICOS, were discovered by functionaleffects on augmenting T cell proliferation following the addition ofmonoclonal antibodies (Hutloff et al. Nature (1999); 397:263-266; Hansenet al. Immunogenics (1980); 10:247-260). PD-1 was discovered throughscreening for differential expression in apoptotic cells (Ishida et al.EMBO J (1992); 11:3887-95). The other members of the family, CTLA-4 andBTLA, were discovered through screening for differential expression incytotoxic T lymphocytes and TH1 cells, respectively. CD28, ICOS andCTLA-4 all have an unpaired cysteine residue allowing forhomodimerization. In contrast, PD-1 is suggested to exist as a monomer,lacking the unpaired cysteine residue characteristic in other CD28family members.

The PD-1 gene is a 55 kDa type I transmembrane protein that is part ofthe Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72). PD-1contains a membrane proximal immunoreceptor tyrosine inhibitory motif(ITIM) and a membrane distal tyrosine-based switch motif (ITSM) (Thomas,M. L. (1995) J Exp Med 181:1953-6; Vivier, E and Daeron, M (1997)Immunol Today 18:286-91). Although structurally similar to CTLA-4, PD-1lacks the MYPPPY motif that is critical for B7-1 and B7-2 binding. Twoligands for PD-1 have been identified, PD-L1 and PD-L2, that have beenshown to downregulate T cell activation upon binding to PD-1 (Freeman etal. (2000) J Exp Med 192:1027-34; Latchman et al. (2001) Nat Immunol2:261-8; Carter et al. (2002) Eur J Immunol 32:634-43). Both PD-L1 andPD-L2 are B7 homologs that bind to PD-1, but do not bind to other CD28family members. PD-L1 is abundant in a variety of human cancers (Dong etal. (2002) Nat. Med. 8:787-9). The interaction between PD-1 and PD-L1results in a decrease in tumor infiltrating lymphocytes, a decrease inT-cell receptor mediated proliferation, and immune evasion by thecancerous cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al.(2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004)Clin. Cancer Res. 10:5094-100). Immune suppression can be reversed byinhibiting the local interaction of PD-1 with PD-L1, and the effect isadditive when the interaction of PD-1 with PD-L2 is blocked as well(Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al.(2003) J. Immunol. 170:1257-66).

Consistent with PD-1 being an inhibitory member of the CD28 family, PD-1deficient animals develop various autoimmune phenotypes, includingautoimmune cardiomyopathy and a lupus-like syndrome with arthritis andnephritis (Nishimura et al. (1999) Immunity 11:141-51; Nishimura et al.(2001) Science 291:319-22). Additionally, PD-1 has been found to play arole in autoimmune encephalomyelitis, systemic lupus erythematosus,graft-versus-host disease (GVHD), type I diabetes, and rheumatoidarthritis (Salama et al. (2003) J Exp Med 198:71-78; Prokunina andAlarcon-Riquelme (2004) Hum Mol Genet 13:R143; Nielsen et al. (2004)Lupus 13:510). In a murine B cell tumor line, the ITSM of PD-1 was shownto be essential to block BCR-mediated Ca²⁺-flux and tyrosinephosphorylation of downstream effector molecules (Okazaki et al. (2001)PNAS 98:13866-71).

“Programmed Death Ligand-1 (PD-L1)” is one of two cell surfaceglycoprotein ligands for PD-1 (the other being PD-L2) that downregulateT cell activation and cytokine secretion upon binding to PD-1. The term“PD-L1” as used herein includes human PD-L1 (hPD-L1), variants,isoforms, and species homologs of hPD-L1, and 5 analogs having at leastone common epitope with hPD-L1. The complete hPD-L1 sequence can befound under GenBank Accession No. Q9NZQ7.

IIa. Anti-LAG-3 Antibodies

Anti-human-LAG-3 antibodies (or VH/VL domains derived therefrom)suitable for use in the invention can be generated using methods wellknown in the art. Alternatively, art recognized anti-LAG-3 antibodiescan be used. For example, the anti-human LAG-3 antibody described inUS2011/0150892 A1, the teachings of which are hereby incorporated byreference, and referred to as monoclonal antibody 25F7 (also known as“25F7” and “LAG3.1) can be used. Other art recognized anti-LAG-3antibodies that can be used include IMP731 described in US 2011/007023,the teachings of which also are hereby incorporated by reference.

Antibodies that compete with any of the above-referenced art-recognizedantibodies for binding to LAG-3 also can be used.

An exemplary anti-LAG-3 antibody is BMS-986016 comprising heavy andlight chains comprising the sequences shown in SEQ ID NOs:1 and 2,respectively, or antigen binding fragments and variants thereof, asdescribed in PCT/US13/48999, the teachings of which are herebyincorporated by reference.

In other embodiments, the antibody has the heavy and light chain CDRs orvariable regions of BMS-986016. Accordingly, in one embodiment, theantibody comprises CDR1, CDR2, and CDR3 domains of the VH region ofBMS-986016 having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2and CDR3 domains of the VL region of BMS-986016 having the sequence setforth in SEQ ID NO:5. In another embodiment, the antibody comprisesCDR1, CDR2 and CDR3 domains comprising the sequences set forth in SEQ IDNOs:7, 8, and 9, respectively, and CDR1, CDR2 and CDR3 domainscomprising the sequences set forth in SEQ ID NOs:10, 11, and 12,respectively. In another embodiment, the antibody comprises VH and/or VLregions comprising the amino acid sequences set forth in SEQ ID NO:3and/or SEQ ID NO: 5, respectively. In another embodiment, the antibodycomprises heavy chain variable (VH) and/or light chain variable (VL)regions encoded by the nucleic acid sequences set forth in SEQ ID NO:4and/or SEQ ID NO:6, respectively. In another embodiment, the antibodycompetes for binding with and/or binds to the same epitope on LAG-3 asthe above-mentioned antibodies. In another embodiment, the antibodybinds an epitope of human LAG-3 comprising the amino acid sequencePGHPLAPG (SEQ ID NO:14). In another embodiment, the antibody binds anepitope of human LAG-3 comprising the amino acid sequence HPAAPSSW (SEQID NO:15) or PAAPSSWG (SEQ ID NO:16).

In another embodiment, the antibody has at least about 90% variableregion amino acid sequence identity with the above-mentioned antibodies(e.g., at least about 90%, 95% or 99% variable region identity with SEQID NO:3 or SEQ ID NO:5).

IIb. Anti-PD-1 Antibodies

Anti-human-PD-1 antibodies (or VH and/or VL domains derived therefrom)suitable for use in the invention can be generated using methods wellknown in the art. Alternatively, art recognized anti-PD-1 antibodies canbe used. For example, monoclonal antibodies 5C4 (referred to herein asNivolumab or BMS-936558), 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, describedin WO 2006/121168, the teachings of which are hereby incorporated byreference, can be used. Other known PD-1 antibodies includeLambrolizumab (MK-3475) described in WO 2008/156712, and AMP-514described in WO 2012/145493, the teachings of which are herebyincorporated by reference. Further known PD-1 antibodies and other PD-1inhibitors include those described in WO 2009/014708, WO 03/099196, WO2009/114335 and WO 2011/161699, the teachings of which are herebyincorporated by reference. Antibodies that compete with any of theseart-recognized antibodies or inhibitors for binding to PD-1 also can beused.

An exemplary anti-PD-1 antibody is BMS-936558 comprising heavy and lightchains comprising the sequences shown in SEQ ID NOs:17 and 18,respectively, or antigen binding fragments and variants thereof.

In other embodiments, the antibody has heavy and light chain CDRs orvariable regions of BMS-936558. Accordingly, in one embodiment, theantibody comprises CDR1, CDR2, and CDR3 domains of the VH of BMS-936558having the sequence set forth in SEQ ID NO:19, and CDR1, CDR2 and CDR3domains of the VL of BMS-936558 having the sequence set forth in SEQ IDNO:21. In another embodiment, the antibody comprises CDR1, CDR2 and CDR3domains comprising the sequences set forth in SEQ ID NOs:23, 24, and 25,respectively, and CDR1, CDR2 and CDR3 domains comprising the sequencesset forth in SEQ ID NOs:26, 27, and 28, respectively. In anotherembodiment, the antibody comprises VH and/or VL regions comprising theamino acid sequences set forth in SEQ ID NO: 19 and/or SEQ ID NO: 21,respectively. In another embodiment, the antibody comprises heavy chainvariable (VH) and/or light chain variable (VL) regions encoded by thenucleic acid sequences set forth in SEQ ID NO:20 and/or SEQ ID NO:22,respectively. In another embodiment, the antibody competes for bindingwith and/or binds to the same epitope on PD-1 as the above-mentionedantibodies. In another embodiment, the antibody has at least about 90%variable region amino acid sequence identity with the above-mentionedantibodies (e.g., at least about 90%, 95% or 99% variable regionidentity with SEQ ID NO:19 or SEQ ID NO:21).

IIc. Anti-PD-L1 Antibodies

Anti-human-PD-L1 antibodies (or VH and/or VL domains derived therefrom)suitable for use in the invention can be generated using methods wellknown in the art. Alternatively, art recognized anti-PD-L1 antibodiescan be used. For example, human anti-PD-L1 antibodies disclosed in U.S.Pat. No. 7,943,743, the contents of which are hereby incorporated byreference, can be used. Such anti-PD-L1 antibodies include 3G10, 12A4(also referred to as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 11E6,12B7, and 13G4. Other art recognized anti-PD-L1 antibodies which can beused include those described in, for example, U.S. Pat. Nos. 7,635,757and 8,217,149, U.S. Publication No. 2009/0317368, and PCT PublicationNos. WO 2011/066389 and WO 2012/145493, the teachings of which also arehereby incorporated by reference. Antibodies that compete with any ofthese art-recognized antibodies or inhibitors for binding to PD-L1 alsocan be used.

III. Pharmaceutical Compositions

Pharmaceutical compositions suitable for administration to humanpatients are typically formulated for parenteral administration, e.g.,in a liquid carrier, or suitable for reconstitution into liquid solutionor suspension for intravenous administration.

In general, such compositions typically comprise a pharmaceuticallyacceptable carrier. As used herein, the term “pharmaceuticallyacceptable” means approved by a government regulatory agency or listedin the U.S. Pharmacopeia or another generally recognized pharmacopeiafor use in animals, particularly in humans. The term “carrier” refers toa diluent, adjuvant, excipient, or vehicle with which the compound isadministered. Such pharmaceutical carriers can be sterile liquids, suchas water and oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil, glycerol polyethylene glycol ricinoleate, and the like. Water oraqueous solution saline and aqueous dextrose and glycerol solutions maybe employed as carriers, particularly for injectable solutions (e.g.,comprising an anti-LAG-3 or anti-PD-1 antibody). Liquid compositions forparenteral administration can be formulated for administration byinjection or continuous infusion. Routes of administration by injectionor infusion include intravenous, intraperitoneal, intramuscular,intrathecal and subcutaneous. In one embodiment, the anti-LAG-3 and/oranti-PD-1 antibodies are administered intravenously (e.g., in separateformulations or together (in the same formulation or in separateformulations)).

IV. Patient Populations

Provided herein are clinical methods for treating solid tumors cancer(e.g., advanced refractory solid tumors) in human patients using acombination of an anti-LAG-3 antibody and an anti-PD-1 antibody.

Examples of cancers that may be treated using the methods of theinvention, include liver cancer, bone cancer, pancreatic cancer, skincancer, cancer of the head or neck, breast cancer, lung cancer,cutaneous or intraocular malignant melanoma, renal cancer, uterinecancer, ovarian cancer, colorectal cancer, colon cancer, rectal cancer,cancer of the anal region, stomach cancer, testicular 20 cancer, uterinecancer, carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of thesmall intestine, cancer of the endocrine system, cancer of the thyroidgland, cancer of the parathyroid gland, cancer of the adrenal gland,sarcoma of soft tissue, cancer of the urethra, cancer of the penis,solid tumors of 25 childhood, lymphocytic lymphoma, cancer of thebladder, cancer of the kidney or ureter, carcinoma of the renal pelvis,neoplasm of the central nervous system (CNS), primary CNS lymphoma,tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitaryadenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer,environmentally induced cancers including those induced by asbestos,hematologic malignancies 30 including, for example, multiple myeloma,B-cell lymphoma, Hodgkin lymphoma/primary mediastinal B-cell lymphoma,non-Hodgkin's lymphomas, acute myeloid lymphoma, chronic myelogenousleukemia, chronic lymphoid leukemia, follicular lymphoma, diffuse largeB-cell lymphoma, Burkitt's lymphoma, immunoblastic large cell lymphoma,precursor B-lymphoblastic lymphoma, mantle cell lymphoma, acutelymphoblastic leukemia, mycosis fungoides, anaplastic large celllymphoma, T-cell lymphoma, and precursor T-lymphoblastic lymphoma, andany combinations of said cancers. The present invention is alsoapplicable to treatment of metastatic cancers.

In one embodiment, the human patient suffers from non-small cell lungcancer (NSCLC) or a virally-related cancer (e.g., a human papillomavirus (HPV)-related tumor) or gastric adenocarcinoma. In a particularembodiment, the HPV-related tumor is HPV+ head and neck cancer (HNC). Inanother particular embodiment, the gastric adenocarcinoma is associatedwith Epstein-Barr virus (EBV) infection.

Patients can be tested or selected for one or more of the abovedescribed clinical attributes prior to, during or after treatment.

V. Combination Therapy

Combination therapies provided herein involve administration of ananti-LAG-3 antibody and another antibody that blocks an inhibitoryimmune receptor (e.g., a receptor, which upon binding to its naturalligand, inhibits/neutralizes activity, such as cytotoxic activity),particularly an anti-PD-1 antibody, to treat subjects having solidtumors (e.g., advanced refractory solid tumors).

In one embodiment, the invention provides an anti-LAG-3 antibody and ananti-PD-1 antibody in combination according to a defined clinical dosageregimen, to treat subjects having a solid tumor (e.g., an advancedrefractory solid tumor). In a particular embodiment, the anti-LAG-3antibody is BMS-986016. In another embodiment, the anti-PD-1 antibody isBMS-936558. In another embodiment, dosage regimens are adjusted toprovide the optimum desired response (e.g., an effective response).

As used herein, adjunctive or combined administration (coadministration)includes simultaneous administration of the compounds in the same ordifferent dosage form, or separate administration of the compounds(e.g., sequential administration). Thus, the anti-LAG-3 and anti-PD-1antibodies can be simultaneously administered in a single formulation.Alternatively, the anti-LAG-3 and anti-PD-1 antibodies can be formulatedfor separate administration and are administered concurrently orsequentially (e.g., one antibody is administered within about 30 minutesprior to administration of the second antibody).

For example, the anti-PD1 antibody can be administered first followed by(e.g., immediately followed by) the administration of the anti-LAG-3antibody, or vice versa. In one embodiment, the anti-PD-1 antibody isadministered prior to administration of the anti-LAG-3 antibody. Inanother embodiment, the anti-PD-1 antibody is administered afteradministration of the anti-LAG-3 antibody. In another embodiment, theanti-LAG-3 antibody and anti-PD-1 antibody are administeredconcurrently. Such concurrent or sequential administration preferablyresults in both antibodies being simultaneously present in treatedpatients.

VI. Treatment Protocols

Suitable treatment protocols for treating a solid tumor in a humanpatient include, for example, administering to the patient an effectiveamount of each of:

(a) an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3 domains of theheavy chain variable region having the sequence set forth in SEQ IDNO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable regionhaving the sequence set forth in SEQ ID NO:5,

(b) an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3 domains of theheavy chain variable region having the sequence set forth in SEQ IDNO:19, and CDR1, CDR2 and CDR3 domains of the light chain variableregion having the sequence set forth in SEQ ID NO:21,

wherein the method comprises at least one administration cycle, whereinthe cycle is a period of eight weeks, wherein for each of the at leastone cycles, at least four doses of the anti-LAG-3 antibody areadministered at a flat dose of about 1, 3, 10, 20, 50, 80, 100, 130,150, 180, 200, 240 or 280 mg and at least four doses of the anti-PD-1antibody are administered at flat dose of about 50, 80, 100, 130, 150,180, 200, 240 or 280 mg. In another embodiment, four doses of theanti-LAG-3 antibody are administered at a dose of 0.01, 0.03, 0.25, 0.1,0.3, 1 or 3, 5, 8 or 10 mg/kg body weight and four doses of theanti-PD-1 antibody are administered at a dose of 0.1, 0.3, 1, 3, 5, 8 or10 mg/kg body weight.

In one embodiment, the anti-LAG-3 antibody and anti-PD-1 antibody areadministered at the following doses:

(a) 3 mg anti-LAG-3 antibody and 80 mg of anti-PD-1 antibody;

(b) 3 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody;

(c) 20 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody;

(d) 80 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody; or

(e) 240 mg anti-LAG-3 antibody and 240 mg of anti-PD-1 antibody.

In another embodiment, the anti-LAG-3 antibody and anti-PD-1 antibodyare administered at the following doses:

(a) 0.3 mg/kg anti-LAG-3 antibody and 1 mg/kg of anti-PD-1 antibody;

(b) 0.3 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody;

(c) 0.25 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody;

(d) 1 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody; or

(e) 3 mg/kg anti-LAG-3 antibody and 3 mg/kg of anti-PD-1 antibody.

In one embodiment, the dose of the anti-LAG-3 and/or anti-PD-1 antibodyis calculated per body weight, e.g., mg/kg body weight. In anotherembodiment, the dose of the anti-LAG-3 and/or anti-PD-1 antibody is aflat-fixed dose. In another embodiment, the dose of the anti-LAG-3and/or anti-PD-1 antibody is varied over time. For example, theanti-LAG-3 antibody and/or anti-PD-1 antibody may be initiallyadministered at a high dose and may be lowered over time. In anotherembodiment, the anti-LAG-3 antibody and/or anti-PD-1 antibody isinitially administered at a low dose and increased over time.

In another embodiment, the amount of the anti-LAG-3 and/or anti-PD-1antibodies administered is constant for each dose. In anotherembodiment, the amount of antibody administered varies with each dose.For example, the maintenance (or follow-on) dose of the antibody can behigher or the same as the loading dose which is first administered. Inanother embodiment, the maintenance dose of the antibody can be lower orthe same as the loading dose.

In another embodiment, the anti-LAG-3 and/or anti-PD-1 antibodies areformulated for intravenous administration. In one embodiment, theanti-PD-1 antibody is administered on Days 1, 15, 29, and 43 of eachcycle. In another embodiment, the anti-LAG-3 antibody is administered onDays 1, 15, 29, and 43 of each cycle.

In other embodiments, the anti-LAG-3 and/or anti-PD-1 antibodies areadministered once per week, once every or three two weeks, once permonth or as long as a clinical benefit is observed or until there is acomplete response, confirmed progressive disease or unmanageabletoxicity.

In another embodiment, a cycle of administration is eight weeks, whichcan be repeated, as necessary. In another embodiment, the treatmentconsists of up to 12 cycles.

In another embodiment, 4 doses of the anti-PD-1 antibody areadministered per eight week cycle. In another embodiment, 4 doses of theanti-LAG-3 antibody are administered per eight week cycle.

In another embodiment, the anti-PD-1 antibody and anti-LAG-3 antibodyare administered as a first line of treatment (e.g., the initial orfirst treatment). In another embodiment, the anti-PD-1 antibody andanti-LAG-3 antibody are administered as a second line of treatment(e.g., after the initial or first treatment, including after relapseand/or where the first treatment has failed).

In another aspect, the invention features any of the aforementionedembodiments, wherein the anti-PD-1 antibody is replaced by, or combinedwith, an anti-PD-L1 or anti-PD-L2 antibody.

VII. Outcomes

With respect to target lesions, responses to therapy may include:

Complete Response (CR) Disappearance of all target lesions. Any (RECISTV1.1) pathological lymph nodes (whether target or non-target) must havereduction in short axis to <10 mm. Partial Response (PR) At least a 30%decrease in the sum of the (RECIST V1.1) diameters of target lesions,taking as reference the baseline sum diameters. Progressive Disease (PD)At least a 20% increase in the sum of the (RECIST V1.1) diameters oftarget lesions, taking as reference the smallest sum on study (thisincludes the baseline sum if that is the smallest on study). In additionto the relative increase of 20%, the sum must also demonstrate anabsolute increase of at least 5 mm. (Note: the appearance of one or morenew lesions is also considered progression). Stable Disease (SD) Neithersufficient shrinkage to qualify for (RECIST V1.1) PR nor sufficientincrease to qualify for PD, taking as reference the smallest sumdiameters while on study. Immune-related Complete Disappearance of alltarget lesions. Any Response (irCR) pathological lymph nodes (whethertarget (irRECIST) or non-target) must have reduction in short axis to<10 mm. Immune-related Partial At least a 30% decrease in the sum ofResponse (irPR) (irRECIST) diameters of target lesions and all newmeasurable lesions (ie Percentage Change in Tumor Burden), taking asreference the baseline sum diameters. Note: the appearance of newmeasurable lesions is factored into the overall Tumor Burden, but doesnot automatically qualify as progressive disease until the sum of thediameters increases by 20% when compared to nadir. Immune-related Atleast a 20% increase in Tumor Burden Progressive Disease (irPD) (ie thesum of diameters of target lesions, (irRECIST) and any new measurablelesions) taking as reference the smallest sum on study (this includesthe baseline sum if that is the smallest on study). In addition to therelative increase of 20%, the sum must also demonstrate an absoluteincrease of at least 5 mm. Tumor assessments using immune-relatedcriteria for progressive disease incorporates the contribution of newmeasurable lesions. Each net percentage change in tumor burden perassessment accounts for the size and growth kinetics of both old and newlesions as they appear. Immune-related Stable Neither sufficientshrinkage to qualify for Disease (irSD) (irRECIST) irPR nor sufficientincrease to qualify for irPD, taking as reference the smallest sumdiameters while on study.

With respect to non-target lesions, responses to therapy may include:

Complete Response (CR) Disappearance of all non-target lesions. (RECISTV1.1) All lymph nodes must be non- pathological in size (<10 mm shortaxis). Non-CR/Non-PD Persistence of one or more non-target (RECIST V1.1)lesion(s). Progressive Disease (PD) Unequivocal progression of existingnon- (RECIST V1.1) target lesions. The appearance of one or more newlesions is also considered progression. Immune-related Disappearance ofall non-target lesions. Complete Response (irCR) All (irRECIST) lymphnodes must be non-pathological in size (<10 mm short axis).Immune-related Increases in number or size of non-target ProgressiveDisease (irPD) lesion(s) does not constitute progressive (irRECIST)disease unless/until Tumor Burden increases by 20% (ie the sum of thediameters at nadir of target lesions and any new measurable lesionsincreases by the required amount). Non-target lesions are not consideredin the definition of Stable Disease and Partial Response.

Patients treated according to the methods disclosed herein preferablyexperience improvement in at least one sign of cancer. In oneembodiment, improvement is measured by a reduction in the quantityand/or size of measurable tumor lesions. In another embodiment, lesionscan be measured on chest x-rays or CT or MRI films. In anotherembodiment, cytology or histology can be used to evaluate responsivenessto a therapy.

In one embodiment, the patient treated exhibits a complete response(CR), a partial response (PR), stable disease (SD), immune-relatedcomplete disease (irCR), immune-related partial response (irPR), orimmune-related stable disease (irSD). In another embodiment, the patienttreated experiences tumor shrinkage and/or decrease in growth rate,i.e., suppression of tumor growth. In another embodiment, unwanted cellproliferation is reduced or inhibited. In yet another embodiment, one ormore of the following can occur: the number of cancer cells can bereduced; tumor size can be reduced; cancer cell infiltration intoperipheral organs can be inhibited, retarded, slowed, or stopped; tumormetastasis can be slowed or inhibited; tumor growth can be inhibited;recurrence of tumor can be prevented or delayed; one or more of thesymptoms associated with cancer can be relieved to some extent.

In other embodiments, administration of effective amounts of theanti-LAG-3 antibody and anti-PD-1 antibody according to any of themethods provided herein produces at least one therapeutic effectselected from the group consisting of reduction in size of a tumor,reduction in number of metastatic lesions appearing over time, completeremission, partial remission, or stable disease. In still otherembodiments, the methods of treatment produce a comparable clinicalbenefit rate (CBR=CR+PR+SD≥6 months) better than that achieved by ananti-LAG-3 antibody or anti-PD-1 antibody alone. In other embodiments,the improvement of clinical benefit rate is about 20% 20%, 30%, 40%,50%, 60%, 70%, 80% or more compared to an anti-LAG-3 antibody oranti-PD-1 antibody alone.

VIII. Kits and Unit Dosage Forms

Also provided herein are kits which include a pharmaceutical compositioncontaining an anti-LAG-3 antibody, such as BMS-986016, and an anti-PD-1antibody, such as BMS-936558, and a pharmaceutically-acceptable carrier,in a therapeutically effective amount adapted for use in the precedingmethods. The kits optionally also can include instructions, e.g.,comprising administration schedules, to allow a practitioner (e.g., aphysician, nurse, or patient) to administer the composition containedtherein to administer the composition to a patient having cancer (e.g.,a solid tumor). The kit also can include a syringe.

Optionally, the kits include multiple packages of the single-dosepharmaceutical compositions each containing an effective amount of theanti-LAG-3 or anti-PD-1 antibody for a single administration inaccordance with the methods provided above. Instruments or devicesnecessary for administering the pharmaceutical composition(s) also maybe included in the kits. For instance, a kit may provide one or morepre-filled syringes containing an amount of the anti-LAG-3 or anti-PD-1antibody.

In one embodiment, the present invention provides a kit for treating asolid tumor in a human patient, the kit comprising:

(a) a dose of an anti-LAG-3 antibody comprising CDR1, CDR2 and CDR3domains of the heavy chain variable region having the sequence set forthin SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chainvariable region having the sequence set forth in SEQ ID NO:5;

(b) a dose of an anti-PD-1 antibody comprising CDR1, CDR2 and CDR3domains of the heavy chain variable region having the sequence set forthin SEQ ID NO:19, and CDR1, CDR2 and CDR3 domains of the light chainvariable region having the sequence set forth in SEQ ID NO:21; and

(c) instructions for using the anti-LAG-3 antibody and anti-PD-1antibody in the methods described herein.

The following examples are merely illustrative and should not beconstrued as limiting the scope of this disclosure in any way as manyvariations and equivalents will become apparent to those skilled in theart upon reading the present disclosure.

The contents of all references, GenBank entries, patents and publishedpatent applications cited throughout this application are expresslyincorporated herein by reference.

EXAMPLES Example 1: Pre-Clinical Pharmacology of Anti-PD-1 Antibody(BMS-936558)

BMS-936558 is a fully human, IgG4 (kappa) isotype monoclonal antibodythat binds to PD-1 with nanomolar affinity as measured by surfaceplasmon resonance using a Biacore® biosensor system and a high degree ofspecificity, thus precluding binding to its ligands PD-L1 and PD-L2.BMS-936558 does not bind other related family members, such as BTLA,CTLA-4, ICOS or CD28. Pre-clinical testing of BMS-936558 demonstratedthat binding to PD-1 results in enhanced T cell proliferation andrelease of interferon-gamma (IFN-gamma) in vitro. The heavy and lightchain amino acid sequences of BMS-936558 are provided in SEQ ID NOs: 1and 2, respectively.

Example 2: In Vivo Toxicity of Anti-PD-1 Antibody Novolumab (BMS-936558)

Toxicology studies in cynomolgus monkeys confirmed that BMS-936558 waswell tolerated at doses up to 50 mg/kg given twice weekly for 27 doses.Drug-related findings were limited to a reversible decrease intriiodothyronine (T3) by 28%, without concomitant abnormalities in othermarkers of thyroid function (data not shown).

Example 3: Clinical Pharmacology and Safety of Anti-PD-1 Antibody(BMS-936558)

The overall safety experience with BMS-936558, as a monotherapy or incombination with other therapeutics, is based on experience inapproximately 1500 subjects treated to date. In general for monotherapy,the safety profile is similar across tumor types. The one exception ispulmonary inflammation adverse events (AEs) which may be numericallygreater in subjects with NSCLC because in some cases, it can bedifficult to distinguish between BMS-936558-related and unrelated causesof pulmonary symptoms and radiographic changes. The safety profile isgenerally consistent across completed and ongoing clinical trials withno maximum tolerated dose reached at any dose tested up to 10 mg/kg.There was no pattern in the incidence, severity, or causality of adverseevents to BMS-936558 dose level.

Study CA209003 has contributed to most of the clinical experience withBMS-936558 in subjects with NSCLC and other solid malignancies to date.CA209003 was a Phase 1 multi-dose escalation study in subjects withpreviously treated advanced or metastatic melanoma, RCC, NSCLC,colorectal cancer, or hormone-refractory prostate cancer. In CA209003,subjects were administered BMS-936558 intravenously every 2 weeks withdoses of 0.1, 0.3, 1, 3, or 10 mg/kg. No maximum tolerated dose wasidentified in CA209003. The maximum dose level evaluated was 10 mg/kg.The incidence, severity, and relationship of adverse events weregenerally similar across dose levels and tumor types.

As of 3 Jul. 2012, 296 (97.4%) out of 304 subjects treated withBMS-936558 had at least 1 reported adverse event regardless ofcausality. There was no pattern in the incidence, severity, orrelationship of adverse events to the BMS-936558 dose level.Treatment-related adverse events of any grade occurred in 220 (72.4%) ofsubjects. The most frequent drug-related adverse events occurring in >5%of subjects included fatigue (25.7%), rash (13.5%), diarrhea (11.8%),pruritus (10.2%), nausea (7.9%), decreased appetite (7.9%), hemoglobindecreased (5.9%), and pyrexia (5.3%). Most treatment-related adverseevents were low grade (Grade 1 or 2). Treatment-related high-grade(Grade 3 or 4) adverse events were reported in 45 (14.8%) of subjects,with the most common being fatigue (1.6%), decreased appetite (1.0%),and diarrhea (1.0%). At least one serious adverse event (SAE) wasreported for 150 (49.3%) of the 304 subjects at all dose levels. Grade3-4 SAEs were reported for 23 subjects (7.6%). Drug-related SAEs of anygrade occurred in 11.5% of subjects. Grade 3-4 drug-related SAEsreported in at least 2 subjects included diarrhea (3 subjects [1.0%]),pneumonitis (3 subjects [1.0%]), pneumonia (2 subjects [0.7%]), andlipase increased (2 subjects [0.7%]). Similar to the overall adverseevent profile, there was no apparent relationship in the incidence orseverity of drug-related adverse events to BMS-936558 dose level. Therewere no apparent differences in the frequency of adverse events based onsubjects' tumor type.

Selected treatment-related adverse events have occurred with lowfrequency (<5%), but are considered clinically meaningful because theyrequire greater vigilance for early recognition and prompt intervention.These adverse events include alanine aminotransferase (ALT) increased(4.3%), aspartate aminotransferase (AST) increased (3.6%), pneumonitis(3.3%), hypothyroidism (3.0%), hyperthyroidism (1.3%), adrenalinsufficiency (0.7%), and colitis (0.7%). Grade 3-4 events ofpneumonitis were reported in 3 subjects (1.0%) as described above (1event was Grade 4). Grade 3 events of colitis, ALT increased, and ASTincreased were reported in 2 subjects (0.7%) each. Grade 3 events ofadrenal insufficiency, hyperthyroidism, and hypothyroidism were reportedin 1 subject (0.3%) each. Because of the potential for clinicallymeaningful BMS-936558-related adverse events requiring early recognitionand prompt intervention, management algorithms have been developed forsuspected pulmonary toxicity, diarrhea or suspected colitis,hepatotoxicity, endocrinopathy, and nephrotoxicity.

Treatment-related adverse events leading to discontinuation werereported in 18 (5.9%) of the 304 treated subjects on CA209003. The onlyevents reported in more than 1 subject were pneumonitis (4 subjects[1.3%]) and hepatitis (2 subjects [0.7%]). There were 3 (1.0%)drug-related deaths; each occurred after the development of pneumonitis.

The safety of BMS-936558 in combination with other therapeutics is beingexplored in several ongoing clinical trials.

Example 4: Pharmacokinetics of Anti-PD-1 Antibody (BMS-936558)

Single-dose pharmacokinetics (PK) of BMS-936558 were evaluated in 39subjects with multiple tumor types in CA209001 in the dose range of 0.3to 10 mg/kg. The median Tmax across dose levels ranged from 1.6 to 3.1hours with individual values ranging from 0.9 to 7 hours. The PK ofBMS-936558 was linear in the range of 0.3 to 10 mg/kg withdose-proportional increase in Cmax and AUC(INF) and low to moderateintersubject variability was observed at each dose level (i.e.,coefficient of variation [CV] ranging from 16 to 45%). Geometric meanclearance (CLT) after a single IV dose ranged from 0.13 to 0.19 mL/h/kg,while mean volume of distribution (Vz) varied between 83 to 113 mL/kgacross doses. The mean terminal T-HALF of BMS-936558 was 17 to 25 days,consistent with half-life of endogenous IgG4, indicating that theelimination mechanism of BMS-936558 may be similar to IgG4. Bothelimination and distribution of BMS-936558 appeared to be independent ofdose within the dose range studied. In a multiple dose study of multipletumor types (CA209003), available data from 128 subjects, mean T-HALFwas 21-24 hours and median T-max ranged from 0.6 to 3.3 across doselevels, which aligns with the single dose data.

Example 5: Phase I Clinical Trial with Anti-PD-1 Antibody (BMS-936558)

BMS-936558 has demonstrated clinical activity in a completed Phase 1single-dose study and 2 ongoing multiple-dose escalation studies (Phase1 monotherapy: CA209003 and Phase 1b combination therapy withipilimumab) in subjects with NSCLC, melanoma, RCC, and othermalignancies. Tumor response was determined by modified ResponseEvaluation Criteria in Solid Tumors (RECIST) established by the NCI. Theevaluable population consists of 294 subjects with a variety of solidtumor malignancies (melanoma, n=138; NSCLC, n=122; RCC, n=34) who arecurrently being treated with nivolumab.

In CA209003, an objective response rate (ORR) of 31.1% (33 of 106response-evaluable subjects) was reported in subjects with melanomatreated with BMS-936558 monotherapy every 2 weeks (Q2W) at doses rangingfrom 0.1 to 10 mg/kg. The majority of responses were durable andexceeded 6 months.

In the most active dose range (3 to 10 mg/kg), an ORR of 13.5% to 27.8%was reported among subjects with NSCLC with a 24-week progression-freesurvival rate (PFSR) of 23% to 51%. Durable responses were observed inboth squamous and non-squamous subtypes.

Of the 34 response-evaluable RCC subjects in CA209003, responses werereported in both the 1-mg/kg (5 of 18 subjects, 27.8%) and 10-mg/kg (5of 16 subjects, 31.3%) treatment groups. Estimated progression-freesurvival rate (PFSR) at 24 weeks was 50% in the 1-mg/kg and 67% in the10-mg/kg BMS-936558 treatment groups.

Preliminary results from the Phase 1b study of combination therapy withBMS-936558 and ipilimumab suggest an advantage in combining two Tcell-targeted therapies for subjects with melanoma. In the 0.3 mg/kgBMS-936558+3 mg/kg ipilimumab treatment group, responses were observedin 5 out of 14 evaluable subjects (35.7%, 1 complete response and 2partial responses by conventional modified World Health Organization[mWHO] criteria, and 2 partial responses by immune-related mWHOcriteria). In the 1 mg/kg BMS-936558+3 mg/kg ipilimumab treatment group,responses were observed in 9 out of 15 evaluable subjects (60%, 3 CRsand 6 PRs; all by conventional mWHO criteria). In the 3 mg/kgBMS-936558+3 mg/kg ipilimumab treatment group, objective responses wereobserved in 4 out of 6 evaluable subjects (66.7%, 3 partial responses byconventional mWHO criteria and 1 partial response by immune-related mWHOcriteria). Further details are provided by Wolchok et al. (2013) NEJM369(2):122-33, and/or PCT/US2013/040764.

Example 6: Pre-Clinical Pharmacology of Anti-LAG-3 Antibody (BMS-986016)

BMS-986016 is a fully human antibody specific for human LAG-3 that wasisolated from immunized transgenic mice expressing human immunoglobulingenes. It is expressed as an IgG4 isotype antibody that includes astabilizing hinge mutation (S228P) for attenuated Fc receptor binding inorder to reduce or eliminate the possibility of antibody- orcomplement-mediated target cell killing. The heavy and light chain aminoacid sequences of BMS-986016 are provided in SEQ ID NOs:17 and 18,respectively.

The ability of BMS-986016 to bind recombinant human LAG-3 antigen wasdetermined using Biacore and enzyme-linked immunosorbent assay (ELISA).Binding to human and primate LAG-3+ transfectants and to activated humanor primate T cells was measured using flow cytometric and Scatchardanalyses. BMS-986016 binds to human LAG-3 with high affinity(K_(D)=0.12-0.5 nM), and inhibits the binding of LAG-3 to cellsexpressing its ligand, MHC class II (IC50, 0.67 nM). BMS-986016 binds tocynomolgus LAG-3 on transfected CHO cells and on activated cynomolgus Tcells with a lower affinity (EC50, 21.5-34.3 nM) than to activated humanT cells. A high concentration of BMS-986016, in the absence of secondaryco-stimulation, elicits no measurable cytokine response from culturedhuman peripheral blood cells nor does the drug mediate measurableantibody-dependent or complement-dependent killing of target cells.BMS-986016 promotes the activation of an antigen-specific mouse T cellhybridoma expressing human LAG-3 in co-culture with an MHC classII-positive antigen-presenting cell. In addition, BMS-986016 enhancesactivation of human T cells in superantigen stimulation assays whenadded alone or in combination with BMS-936558 (anti-PD-1 antibody).

Example 7: Toxicity of Anti-LAG-3 Antibody (BMS-986016) Alone or inCombination with Anti-PD-1 Antibody (BMS-936558)

The following preclinical toxicology studies were performed:

A. Four-Week Intermittent (QW) Intravenous Exploratory CombinationPharmacodynamic and Toxicity Study in Cynomolgus Monkeys withAnti-LAG3.1 Antibody (a Precursor of BMS-986016) and BMS-936558

The key results were as follows. Anti-LAG3.1 administered at 50mg/kg/week, alone or in combination with 50 mg/kg/week BMS-936558, didnot result in any adverse changes. No-observed-adverse-effect level(NOAEL) for single-agent anti-LAG3.1 was considered to be 50 mg/kg/week(AUC[0-168h]=231,000 μg·h/mL), and NOAEL for anti-LAG3.1 in combinationwith 50 mg/kg/week BMS-936558 was considered to be 50 mg/kg/week (meananti-LAG3.1 AUC[0-168h]=210,000 μg·h/mL; meanBMS-936558AUC[0-168h]=159,500 μg·h/mL).

B. GLP-Compliant Four-Week Intravenous Combination Toxicity Study inCynomolgus Monkeys with a 6-Week Recovery with BMS-986016 and BMS-936558

The key results were as follows. Single-agent BMS-986016 administered atup to 100 mg/kg/week did not result in adverse changes. Single-agentBMS-936558 administered at 50 mg/kg/week resulted in slight to minimalnon-reversible lymphoplamacytic inflammation of the choroid plexus ofthe brain, which was considered non-adverse given the lower severity andincidence of the lymphoplamacytic inflammation compared to combinationtreatment with BMS-986016 and BMS-936558, lack of vasculitis or tissuedestruction, and absence of clinical manifestations during the course oftreatment. Combined administration of BMS-986016 and BMS-936558 (100 and50 mg/kg/week, respectively) resulted in morbidity of 1 male out of 9monkeys on study Day 29. From Days 26 to 29, this monkey presented withelevated body temperature, shivers, red or clear nasal discharge, fecalchanges (unformed, scant or absent feces), decreased feeding behavior,mild dehydration, sneezing, decreased activity, and hunched posture.After 2 days of veterinary care and antibiotic treatment, this animaldid not show any improvement and was euthanized on Day 29 for poorclinical condition.

There were no remarkable gross necropsy findings. Histopathologicalfindings in this monkey included: slight lymphoplamacytic inflammationof the choroid plexus; minimal to moderate lymphohistocytic inflammationof the vasculature of the brain parenchyma, meninges, spinal cord(cervical and lumbar); and minimal to moderate mixed cell inflammationof the epididymes, seminal vesicles and testes. Clinical pathologychanges indicated decreases in red blood cell count, hemoglobinconcentration and hematocrit whose cause was unclear, and an increase infibrinogen correlating with the inflammation observed in the centralnervous system (CNS) and male reproductive tract.

Additional histopathological findings upon combination administration ofBMS-986016 and BMS-936558 (100 and 50 mg/kg/week, respectively) werelimited to minimal to slight non-reversible lymphoplamacyticinflammation of the choroid plexus in the brain in 7 of 8 remainingmonkeys, and minimal lymphohistiocytic inflammation of the vasculatureof the brain parenchyma in 1 of 8 remaining monkeys, whose reversibilitycould not be assessed.

NOAEL for single-agent BMS-986016 was considered to be 100 mg/kg/week(mean AUC[0-168h]=474,000 μg·h/mL); NOAEL for single-agent BMS-936558was considered to be 50 mg/kg/week (mean AUC[0-168h]=193,000 μg·h/mL);NOAEL for combination of BMS-986016 and BMS-936558 was not determined.However, the combination therapy was generally well tolerated andclinical signs of toxicity were observed in only 1 of 9 monkeys(approximately 10%). Therefore, 100/50 mg/kg/week BMS-986016/nivolumab(mean BMS-986016 AUC[0-168h]=514,000 μg·h/mL; mean nivolumabAUC[0-168h]=182,000 μg·h/mL) was considered the STD10.

The doses administered (100 mg/kg BMS-986016 and 50 mg/kg BMS-936558)are ≥10 times higher than the maximum doses proposed for the currentstudy. The starting dose of 20 mg (0.25 mg/kg) for BMS-986016monotherapy (Part A) is less than 1/10 of the human equivalent of thecynomolgus monkey NOAEL (636 mg; 8.0 mg/kg), and is below the HED aftera linear adjustment of the NOAEL target exposure for the highestaffinity difference estimate of 265-fold (24 mg; 0.30 mg/kg). Thecalculated safety multiple for exposures at the 20 mg (0.25 mg/kg)starting dose is 315-fold based on the cynomolgus monkey NOAEL of 100mg/kg/week without accounting for affinity differences.

The starting dose of 3 mg (0.03 mg/kg) for BMS-986016 for thecombination therapy (Part B) is based on a linear adjustment of thecynomolgus monkey STD10 for the 265-fold highest affinity differenceestimate with an added 10-fold safety factor. The maximum recommendedstarting dose (MRSD) for BMS-986016 based on a 100 mg/kg/week STD10 is0.03 mg/kg in humans. The starting dose of 80 mg (1 mg/kg) forBMS-936558 for the combination therapy (Part B) is based on known humanBMS-936558 PK parameters with an added 10-fold safety factor. The MRSDfor BMS-936558 based on the 50 mg/kg/week cynomolgus monkey STD10 is 4.3mg/kg in humans, and has been further reduced to identify a dose withacceptable levels of adverse events.

C. GLP-Compliant Tissue Cross Reactivity Study in Human and SelectCynomolgus Monkey Tissues with BMS-986016.

Positive staining with BMS-986016-FITC was observed in the plasmamembrane or plasma membrane granules following human tissues:mononuclear leukocytes of the urinary bladder, blood cells, colon—largeintestine, eye, esophagus, small intestine, stomach, kidney, lung, lymphnode, placenta, salivary gland, skin, spleen, thymus, tonsil,uterus—cervix, and uterus—endometrium; and hematopoetic cells of thebone marrow. In addition, staining with BMS-986016-FITC was observed inthe cytoplasm of the human pituitary endocrine cell epithelium. Withinthe limited panel of cynomolgus monkey tissues evaluated, staining withBMS-986016-FITC was observed in the plasma membrane or plasma membranegranules of the mononuclear leukocytes of the spleen. With scientificreports of LAG-3-expressing cells in germinal centers andinterfollicular T-cell areas of normal human lymphoid tissues (lymphnode, tonsil, spleen, thymus, bone marrow and mucosal-associatedlymphoid tissue) and having the morphology and distribution oflymphocytes, the staining of mononuclear leukocytes and hematopoieticcells with BMS-986016-FITC in this study (in the human and cynomolgusmonkey tissues) was anticipated. Given that LAG-3 mRNA is expressed inthe human pituitary and LAG3.1-G4P-FITC staining was observed inadenohypophysis of the human pituitary in a pilot tissue crossreactivity study, BMS-986016-FITC staining of human pituitary endocrinecell epithelium cytoplasm and cytoplasmic granules was also anticipated.Although BMS-986016 is not expected to have access to the cytoplasmiccompartment in vivo and the repeat-dose toxicology studies in monkeysshowed no effects on the pituitary gland, these findings may be ofclinical significance.

D. In Vitro Cytokine Release and Lymphocyte Activation Assessment withBMS-986016 Using Human Peripheral Blood Mononuclear Cells.

BMS-986016 did not induce cytokine release when presented to human PBMCsregardless of concentration, donor, or incubation time. The levels ofcytokines observed were either at or near the assay lower limits ofquantification with no evidence of dose-dependence or pattern acrossdonors (IL-1β, IL-2, IL-5, IL-10, IL-12p70, and IFN-γ) or were generallyoverlapping with cytokine levels from PBMCs incubated with negativecontrols (IL-6, IL-8, TNF-α).

Consistent with the lack of cytokine release, there was no evidence thatBMS-986016 induced T or NK cell activation, as measured by surfaceexpression of CD25 and CD69. Expression levels of these markers on T andNK cells following stimulation with BMS-986016 were similar to thoseobserved upon stimulation with negative controls.

Overall, these data indicate that BMS-986016 does not possess agonisticpotential to induce either T or NK cellular activation or cytokinerelease.

Example 8: Preclinical Pharmacokinetics of Anti-LAG-3 Antibody(BMS-986016)

In accordance with regulatory guidelines for biotechnology-derivedpharmaceuticals (ICH Harmonised Tripartite Guideline, S6(R1) PreclinicalSafety Evaluation of Biotechnology-Derived Pharmaceuticals.International Conference on Harmonisation, 2011), no metabolism studieswith BMS-986016 have been conducted in animals. The expected in vivodegradation of monoclonal antibodies (mAbs) is to small peptides andamino acids via biochemical pathways that are independent of cytochromeP450 enzymes.

BMS-986016 demonstrated favorable pharmacokinetic (PK) properties incynomolgus monkeys. From both single-dose and repeat-dose IV PK studies,BMS-986016 decayed bi-exponentially and the exposure was approximatelydose-proportional. The systemic clearance (CLTp) ranges from 0.12 to0.22 mL/h/kg and a terminal half-life (T-HALF) 133 to 414 hours. Thevolume of distribution at steady state (Vss) was 62 to 72 mL/kg,suggesting limited distribution outside the plasma. Anti-BMS-986016antibodies were detected in some monkeys but the presence ofanti-BMS-986016 antibodies appeared to have no impact on BMS-986016exposure.

Example 9: Inhibition of Tumor Growth In Vivo by Combination Treatmentwith Anti-LAG-3 Antibody and Anti-PD-1 Antibody

An experiment was conducted in a murine tumor model to test thehypothesis that the combination of anti-LAG-3 and anti-PD-1 wouldpotentiate anti-tumor efficacy. These studies evaluated tumor growthinhibition in syngeneic tumor models (Sa1N fibrosarcoma and MC38 colonadenocarcinoma) and monitored acceleration of autoimmunity in thenon-obese diabetic (NOD) model. Anti-LAG-3 antibody administrationresulted in both overall tumor growth inhibition and an increase in thenumber of tumor-free (TF) mice in those treatment groups, as shown inFIG. 1. Anti-LAG-3 antibody administered in combination with anti-PD-1antibody provided enhanced anti-tumor activity above the activity ofeither agent alone. For example, in multiple Sa1N tumor models,anti-LAG-3 antibody resulted in 20%-30% TF mice compared to control andanti-PD-1 antibody-treated mice (0%-10% TF mice), while the combinationof anti-LAG-3 and anti-PD-1 antibodies resulted in 60%-90% TF mice. Inthe MC38 model, anti-LAG-3 antibody showed modest tumor growthinhibition alone, but when administered in combination with anti-PD-1antibody, resulted in enhanced antitumor activity above that observedfor anti-PD-1 antibody alone (80% vs. 40% TF mice, respectively).

Example 10: Phase 1 Trial in Patients Having Solid Tumors

A phase 1 trial of anti-LAG-3 antibody (BMS-986016) and anti-PD-1antibody (BMS-936558) is conducted in patients having advanced solidtumors to demonstrate the efficacy of administering BMS-986016 andBMS-936558 as a combination treatment.

1. Objectives

The primary objective of the study is to assess the safety andtolerability of BMS-986016 given in combination with BMS-936558 and toidentify dose limiting toxicities (DLTs) and the maximally tolerateddose (MTD) of the combination, in subjects with advanced solid tumors.

Secondary objectives include assessing the preliminary anti-tumoractivity of the combination of BMS-986016 and BMS-936558 in subjectswith advanced solid tumors, characterizing the pharmacokinetics (PK) ofBMS-986016 and BMS-936558 when co-administered, monitoringimmunogenicity of BMS-986016 and BMS-936558 administered as combinationtherapy, and assessing the effect of BMS-986016 and BMS-936558 oncorrected QT (“QTc”). Additional exploratory objectives includeassessing the pharmacodynamic effects of BMS-986016 and BMS-936558combination therapy based on select biomarkers in the peripheral bloodand tumor biopsy specimens, characterizing T cell function duringBMS-986016 and BMS-936558 combination therapy, assessing the 2-yearlandmark overall survival in subjects treated with BMS-986016 andBMS-936558, exploring preliminary antitumor activity of BMS-986016 andBMS-936558 combination therapy in subjects with advanced solid tumors,characterizing pharmacokinetics and exposure-response relationships insubjects treated with BMS-986016 and BMS-936558, and investigating therelationship between clinical efficacy and selected peripheral and tumorbiomarkers.

2. Study Design and Duration

This is a Phase 1, open-label study of BMS-986016 administered as asingle agent and in combination with BMS-936558 (nivolumab) to subjectswith advanced solid tumors. The study is conducted in 3 parts. Part Aand Part B consist of a 3+3+3 dose escalation design with BMS-986016administered as a single agent (Part A) or in combination withBMS-936558 (Part B) in subjects with advanced solid tumors. Treatment inPart B is initiated upon the decision to escalate to the third dosecohort in Part A (in accordance with dose escalation rules).Subsequently, escalation in the 2 parts proceeds in parallel. At nopoint does the dose of BMS-986016 administered in combination withBMS-936558 (Part B) exceed doses of BMS-986016 that have beendemonstrated previously to be safe on the monotherapy dose escalationarm (Part A). Part C consists of cohort expansion in 6disease-restricted populations of approximately 16 subjects each, withBMS-986016 administered in combination with BMS-936558. Treatment inPart C is initiated when the maximum tolerated dose (MTD) (or maximumadministered dose (MAD) if no MTD is determined) for Part B has beendetermined. The doses selected for Part C do not exceed the Part B MTDor MAD, but dose determination may incorporate assessment of other data,including toxicities and PK and pharmacodynamic data from Parts A and B.A schematic of the study is provided in FIG. 2.

Subjects complete up to 4 periods of the study as follows: Screening (upto 28 days), Treatment (up to a maximum of twelve 8-week cycles of studytherapy), Clinical Follow-up (135 days), and Survival Follow-up (up to 2years following the first dose of study drug; a longer follow-up periodcould be considered in selected cases if an efficacy signal isapparent). During this period, diagnostic imaging may be performed every12 weeks until progression in subjects who discontinue due to CR, and insubjects with PR at the end of Cycle 12.

The Treatment Period consists of up to twelve 8-week treatment cycles.Each treatment cycle is comprised of 4 doses of either BMS-986016 alone(Part A) or in combination with BMS-936558 (Parts B and C), administeredon Days 1, 15, 29, and 43 of each treatment cycle. In Parts B and C whenboth antibodies are administered in combination, nivolumab will be givenfirst followed by BMS-986016 within 30 minutes of completing theinfusion of nivolumab. Tumor response is evaluated using RECIST v1.1.Subjects are allowed to continue study therapy until the occurrence ofeither: (1) confirmed complete response (CR), (2) completion of themaximum number of twelve 8-week cycles, (3) progressive disease (PD),(4) clinical deterioration, and/or (5) meeting other criteria fordiscontinuation. Treatment beyond progression is allowed in selectsubjects with initial RECIST v1.1-defined PD who are receiving clinicalbenefit and tolerating treatment. Subjects who discontinue treatmententer a 135-day Clinical Follow-up period.

After completion of the Clinical Follow-up period, subjects enter theSurvival Follow-up period. During this period, clinic visits ortelephone contact every 12 weeks are performed to assess survivalstatus. The duration of this period is up to 2 years following the firstdose of study drug, although a longer follow-up period is considered inselected cases if an efficacy signal is apparent. Subjects in theSurvival Follow-up period who have disease progression are allowed toreceive tumor-directed therapy as required. A study schematic isdepicted in FIG. 3.

Assessments, including physical examinations, vital sign measurements,12-lead ECG, and clinical laboratory evaluations are performed atselected times throughout the dosing interval. Subjects are closelymonitored for adverse events throughout the study. Blood samples arecollected for up to 4 hours following the start of study drugadministration for pharmacokinetic analysis.

Subjects are allowed to continue on therapy for up to twelve 8-weekcycles or until confirmed complete response, progressive disease,clinical deterioration, or meeting criteria for discontinuation.Subjects may be on study for a total of up to approximately 2.3 years,including a 28-day screening period, up to twelve 8-week cycles oftreatment, a 135-day clinical follow-up period, and up to 2 years offollow-up for survival (beginning from the first dose of study drug).The total duration of the study is expected to be approximately 5 yearsfrom the time of the first visit of the first subject to the requiredsurvival follow-up of the last subject enrolled.

3. Dose Escalation

Part A

In Part A, a 3+3+3 design is used to assess the safety of BMS-986016given as single agent. A fourth subject may be enrolled at the beginningof a dose escalation cohort, if subject is able to start the first dayof dosing within approximately one week of the third subject in the samedose escalation cohort. The dosages during dose escalation are providedin FIGS. 2A and 2B and Table 1 (set forth below). Three subjects (or 4,if applicable) are initially treated in each dose cohort. In Dose Cohort1, each of the first 3 subjects (or 4, if applicable) is designated assentinel subjects and begin a treatment at least 5 days apart. Subjectsin subsequent cohorts are not required to observe the 5-day intervalbetween treatment start dates. Dose escalation in Part A proceeds asfollows:

-   -   If 0 of the first 3 subjects (or 4, if applicable) experience a        dose-limiting toxicity (DLT) within the DLT evaluation interval,        a new cohort of 3 subjects (or 4, if applicable) is treated at        the next higher dose level.    -   If 1 of 3 subjects (or 4, if applicable) experience a DLT within        the DLT evaluation interval, that cohort is expanded to 6        subjects.    -   If 2 of 6 subjects experience a DLT within the DLT evaluation        interval, that cohort is expanded to 9 subjects.    -   If ≥2 of 3 (or 4, if applicable), ≥3 of 6, or ≥3 of 9 subjects        experience DLTs within a dose cohort during the DLT evaluation        interval, then that dose level is determined to have exceeded        the MTD.

TABLE 1 Dose Escalation Schedule for Part A - BMS-986016 MonotherapyBMS-986016 Dose Dose Cohort Number Total Subjects (IV; mg) 1 n =approximately 3-9 20 2 n = approximately 3-9 80 3 n = approximately 3-9240 4 n = approximately 3-9 800 Total N = approximately 12-36

Prior to declaring the MTD (or MAD), any cohort previously establishedto be safe is expanded to obtain additional experience or to investigatedose levels intermediate to those defined in the protocol. Doseescalation rules (cohort size, DLT evaluation interval, cohort expansioncriteria, etc.) apply to these expanded or additional cohorts. A maximumof 9 subjects are enrolled in any additional or expanded dose cohorts.

No within-subject dose escalations are permitted. If a dose level isfound to exceed the MTD, subjects enrolled in that dose level aretreated at a lower dose.

Part B

Treatment in Part B is initiated after the decision is made to escalateto the third dose cohort in Part A (in accordance with dose escalationrules). Subsequently, escalation in the 2 parts proceeds in parallel. Atno point does the dose of BMS-986016 administered in combination withBMS-936558 (Part B) exceed doses of BMS-986016 that have beendemonstrated previously to be safe on the monotherapy dose escalationarm (Part A). Treatment assignments for subjects eligible for both PartA and Part B alternates between the 2 parts, with consecutively treatedsubjects assigned to different parts through interactive voice responsesystem (IVRS) whenever possible. If there are no openings available inthe part to which the subject is assigned by this algorithm, the subjectis assigned to the next open cohort or part. As in Part A, a 3+3+3design is also be used in Part B to assess the safety of BMS-986016given in combination with nivolumab. A fourth subject may be enrolled atthe beginning of a dose escalation cohort, if subject is able to startthe first day of dosing within approximately one week of the thirdsubject in the same dose escalation cohort. The dosages evaluated duringdose escalation are provided in FIGS. 2A and 2B and Table B (set forthbelow). As in Part A, each of the first 3 subjects (or 4, if applicable)in the first dose cohort in Part B will be designated as sentinelsubjects and will begin treatment at least 5 days apart.

TABLE 2 Dose Escalation Schedule for Part B - BMS-986016 in Combinationwith BMS-936558 BMS-986016 BMS-936558 Dose Cohort Dose Dose Number TotalSubjects (IV; mg) (IV; mg) 1 n = approximately 3-9 3 80 2 n =approximately 3-9 3 240 3 n = approximately 3-9 20 240 4 n =approximately 3-9 80 240 5 n = approximately 3-9 240 240 Total N =approximately 15-45

Three subjects are treated initially in each dose cohort. In Dose Cohort1, each of the first 3 subjects, designated as sentinel subjects, beginstreatment at least 5 days apart. Subjects in subsequent cohorts are notbe required to observe the 5-day interval between treatment start dates.

Dose escalation in Part B proceeds as described for Part A. If the MTDis exceeded in Dose Cohort 2, the subsequent cohort is treated with 20mg of BMS-986016 and 80 mg of BMS-936558. If this dose combination isfound to be safe, escalation proceeds at the previously definedBMS-986016 doses, maintaining the BMS-936558 dose at 80 mg.

If no MTD is reached through Dose Cohort 5, then additional cohorts ofBMS-986016 given in combination with BMS-936558 are considered based onthe aggregate safety experience during dose escalation.

Prior to declaring the MTD (or MAD), any cohort previously establishedto be safe is expanded in order to obtain additional experience or toinvestigate dose levels intermediate to those defined in the protocol.Dose escalation rules (cohort size, DLT evaluation interval, cohortexpansion criteria, etc.) apply to these expanded or additional cohorts.A maximum of 9 subjects are enrolled in any additional or expanded dosecohorts.

No within-subject dose escalations are permitted. If a dose level isfound to exceed the MTD, subjects enrolled in that dose level arereduced to a lower dose.

4. Cohort Expansion

The purpose of cohort expansion is to gather additional safety,tolerability, preliminary efficacy, pharmacokinetic, and pharmacodynamicinformation regarding the combination of BMS-986016 and BMS-936558. Thedoses selected for Part C do not exceed the MTD (or MAD if no MTD isdetermined) in Part B, but may incorporate assessment of other dataincluding toxicities and PK and pharmacodynamic data from Parts A and B.Doses include doses intermediate to those evaluated in Part B. Modelingis used to help inform the selection of the combination dose level tocarry forward in Part C if a dose below the MTD is chosen. Six expansioncohorts are restricted to the tumor types listed below in Tables 3A and3B. Continuous evaluation of toxicity events in the cohort expansions isperformed throughout enrollment in the expansion cohorts. If, at anytime, the aggregate rate of treatment-related toxicities meeting DLTcriteria exceeds 33% across all subjects treated in the Part C cohortexpansion, further enrollment is interrupted. Depending on the natureand grade of the toxicity and after assessing the risk:benefit ratio, anew dose(s) for all cohorts is initiated at a previously tested lowerdose level or at a dose level intermediate to previously tested lowerdose levels.

Upon determination of the MTD (or MAD if no MTD is determined) in PartA, a BMS-986016 monotherapy cohort is evaluated in cohort expansion.This expansion cohort is restricted to the tumor type(s) found to beresponsive to BMS-986016 monotherapy. The dose selected for monotherapyexpansion does not exceed the Part A MTD (or MAD if no MTD isdetermined) and incorporates assessment of other data, includingtoxicities and PK and pharmacodynamic data from Part A. The doseselected is intermediate to those tested in Part A. Modeling is used tohelp inform the selection of the dose level to carry forward in Part Cif a dose below the MTD is chosen.

TABLE 3A Tumor Types Eligible For Part C - Cohort Expansion CombinationTherapy Tumor Type Total Subjects Melanoma: naive to ICMARs^(a)approximately 16 Melanoma: anti-PD-1 or anti-PD-L1 antibodyapproximately 16 as most recent therapy^(b) NSCLC^(c): naive toICMARs^(a) approximately 16 NSCLC^(c): anti-PD-1 or anti-PD-L1 antibodyas approximately 16 most recent therapy^(b) HPV^(d)-positive head andneck cancer naive to approximately 16 ICMARs^(a) Gastric adenocarcinomanaive to ICMARs^(a) approximately 16 Total approximately 96 ^(a)ICMARs:immune cell-modulating antibody regimens (such as, but not limited to,ipilimumab, tremelimumab, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-KIR,anti-CD137, and/or anti-OX40 antibodies) ^(b)Subjects with anti-PD-1 oranti-PD-L1 antibody as most recent therapy are nonresponsive subjectswith progression within 16 weeks of starting therapy. Subjects mustprovide informed consent within 60 days after the last dose of anti-PD-1or anti-PD-L1 antibody and should not have discontinued antibody therapydue to serious and/or life-threatening toxicity (e.g., dose-limitingtoxicity in prior study). Subjects with anti-PD-1 or anti-PD-L1 antibodyas most recent therapy cannot have had prior exposure to any otherICMARs. ^(c)NSCLC: non-small cell lung cancer ^(d)HPV: human papillomavirus

TABLE 3B Tumor Types Eligible For Part C - Cohort Expansion CombinationTherapy Tumor Type Total Subjects Melanoma: naive to ICMARs^(e)approximately 16 Melanoma: prior anti-CTLA-4 and anti-PD-1 orapproximately 16 anti-PD-L1 antibody therapy^(f) NSCLC^(g): naive toICMARs^(a) approximately 16 NSCLC^(c): anti-PD-1 or anti-PD-L1 antibodyas approximately 16 most recent therapy^(b) Head and neck cancer naiveto ICMARs^(a) approximately 16 Gastric adenocarcinoma naive toICMARs^(a) approximately 16 Total approximately 96 ^(a)ICMARs: immunecell-modulating antibody regimens (such as, but not limited to,anti-CTLA-4, and anti-PD-1 or anti-PD-L1, anti-PD-L2, anti-KIR,anti-CD137, and/or anti-OX40 antibodies) ^(b)Melanoma subjectsprogressing while-on or after receiving anti-CTLA-4 and anti-PD-1 oranti-PD-L1 antibody therapies (in sequential or combination regimens),are eligible. Non-eligible melanoma subjects in this group include thosewith: 1) last does of anti-CTLA-4 antibody therapy received within 100days of first dose of study medication; 2) prior exposure to ICMARsother than anti-CTLA-4, anti-PD-1 or anti-PD-L1 antibody therapyregimens; 3) discontinuation from anti-CTLA-4, anti-PD-1 or anti-PD-L1antibody therapy due to serious and/or life-threatening toxicity (e.g.,dose-limiting toxicity in prior exposure). ^(c)NSCLC: non-small celllung cancer ^(d)NSCLC subjects whose disease progresses while-on orafter therapy with anti-PD-1 or anti-PD-L1 antibody as most recenttherapy. Subject should not have discontinued antibody therapy due toserious and/or life-threatening toxicity (e.g., dose-limiting toxicityin prior study). Subjects with anti-PD-1 or anti-PD-L1 antibody as mostrecent therapy cannot have had prior exposure to any other ICMARs.

5. Dose Limiting Toxicities

BMS-986016 has the potential to augment the frequency and severity ofpreviously described adverse events associated with BMS-936558, or toproduce new toxicities. For the purpose of guiding decisions regardingdose escalation in Part A and Part B, dose-limiting toxicity (DLT) isdetermined based on the incidence, intensity, and duration of adverseevents that are related to study drug and that occur within 56 days (8weeks) of initiation of study drug (i.e., the DLT evaluation interval,through the completion of Cycle 1). The severity of adverse events isgraded according to National Cancer Institute (NCI) Common TerminologyCriteria for Adverse Events (CTCAE) v4.0. For the purpose of subjectmanagement, DLTs that occur at any time, whether during dose escalation(Part A and Part B) or cohort expansion (Part C) result in all studydrug(s) being held, pending evaluation of the event's relatedness tostudy drug. Subjects must meet criteria for re-treatment prior tore-initiation of study treatment.

Subjects who withdraw from the study during the DLT evaluation intervalfor reasons other than a DLT may be replaced at the same dose level. Inthe case that an infusion cannot be administered at a scheduled visitduring the DLT evaluation interval, it must be administered as soon aspossible. If the delay is between 1 and 7 days, the procedures at theoriginal scheduled visit should be performed and subjects will beconsidered evaluable for DLT determination. If the delay is more than 7days, the dose will be considered missed and will not be replaced. Forthe purpose of making decisions on dose escalation from a safetyperspective, subjects will be considered evaluable if they have received3 out of the 4 scheduled BMS-986016 doses in Part A (or 3 out of 4schedules BMS-986016 and nivolumab doses in Part B) through the 8 weekobservation period, only if the one missed dose was secondary toprogressive disease or non-medical reasons. Unevaluable subjects may bereplaced at the same dose level.

Hepatic, non-hematologic, and hematologic DLTs are defined separately asoutlined below.

Hepatic DLT

Any of the following drug-related events are considered a hepatic DLT:

-   -   ALT or AST>8×ULN, regardless of duration, or    -   ALT or AST>5× and ≤8×ULN, that fails to return to ≤Grade 1        within 2 weeks despite medical intervention, or    -   Total bilirubin >5×ULN, or    -   ALT or AST>3×ULN and concurrent total bilirubin >2×ULN

Non-Hematologic DLT

Any of the following drug-related events are considered anon-hematologic DLT:

-   -   Grade 2 immune related-eye pain or reduction in visual acuity        that requires systemic treatment, or    -   Grade 2 eye pain or reduction in visual acuity that does not        respond to topical therapy and that does not improve to Grade 1        within 2 weeks of initiation of topical therapy, or    -   ≥Grade 3 non-hepatic or non-hematologic toxicity with the        exceptions noted below.

The following Grade 3 non-hematologic events are not considered DLTs:

-   -   Grade 3 electrolyte abnormality that lasts <72 hours, is not        clinically complicated, and resolves spontaneously or responds        to conventional medical intervention    -   Grade 3 increase in amylase or lipase that persists for <3 weeks        and is not associated with clinical or radiographic evidence of        pancreatitis    -   Grade 3 nausea or vomiting that lasts <48 hours, and resolves to        ≤Grade 1 either spontaneously or with conventional medical        intervention    -   Grade 3 fever that lasts <72 hours, and is not associated with        hemodynamic compromise (including hypotension, or clinical or        laboratory evidence of end organ perfusion impairment)    -   Grade 3 endocrinopathy that is well controlled by hormone        replacement    -   Grade 3 tumor flare (defined as pain, irritation, or rash that        localizes to sites of known or suspected tumor)    -   Grade 3 fatigue for less than 7 days

Hematologic DLT

Any of the following drug-related events are considered a hematologicDLT:

-   -   Grade 4 febrile neutropenia of any duration    -   Grade 4 neutropenia that lasts >5 days    -   Grade 4 thrombocytopenia    -   Grade 4 anemia    -   Grade 3 thrombocytopenia associated with clinically significant        bleeding    -   Grade 3 febrile neutropenia that lasts >48 hours    -   Grade 3 hemolysis

6. Inclusion Criteria

Signed Written Informed Consent

The subject must sign and date the IRB/IEC approved written informedconsent form prior to the performance of any study-related proceduresthat are not considered part of standard of care.

Consent for tumor biopsy samples for Part A or Part B Dose Escalation:Subject must consent to allow the acquisition of existing formalin-fixedparaffin-embedded (FFPE) tumor tissue, either a block or unstainedslides, for performance of correlative studies. If an archived sample isnot available, subject must consent to allow a pre-treatment tumorbiopsy. In either case, study personnel must ensure that the tissueblock or slides physically exist prior to initiating therapy. Subjectsunable to provide an archived tumor sample and who either do not consentto a pre-treatment tumor biopsy or do not have accessible lesions arenot eligible. (However, subjects whose pre-treatment biopsy yieldsinadequate tissue quantity or quality are not ineligible on this basisalone.)

Consent for tumor biopsy samples for Part C Cohort Expansion: Subjectswith melanoma or head and neck tumors: All subjects in the 2 melanomacohorts and all subjects in the head and neck tumor cohort are requiredto undergo pre-treatment and on-treatment biopsies; therefore, subjectsmust have a lesion located such that the specimen can be obtained atacceptable clinical risk as judged by the Investigator. Biopsy sites forany subjects must be distinct from evaluable lesions. Subjects in themelanoma and head and neck cancer cohorts who do not meet these criteriaare not eligible; however, subjects whose screening biopsy yieldsinadequate tissue quantity or quality are not be ineligible on thisbasis alone. Subjects in the remaining cohorts (NSCLC or gastricadenocarcinoma): Subject must consent to allow the acquisition ofexisting formalin-fixed paraffin-embedded (FFPE) tumor tissue, either ablock or unstained slides, for performance of correlative studies. If anarchived sample is not available, subject must consent to allow apre-treatment tumor biopsy. In either case, study personnel must ensurethat the tissue block or slides physically exist prior to initiatingtherapy. Subjects unable to provide an archived tumor sample and whoeither do not consent to a pre-treatment tumor biopsy or do not haveaccessible lesions are not eligible. (However, subjects whosepre-treatment biopsy yields inadequate tissue quantity or quality arenot ineligible on this basis alone.) Biopsies cannot be collected insubjects with a single measurable lesion, even if accessible.

Target Population

-   -   a) Subjects must have histologic or cytologic confirmation of an        incurable solid malignancy that is advanced (metastatic and/or        unresectable):        -   i) Part A Dose Escalation: BMS-986016 monotherapy            -   (1) All solid tumor histologies are permitted except for                subjects with primary CNS tumors            -   (2) Only subjects without prior exposure to immune                cell-modulating antibody regimens (ICMARs) such as, but                not limited to, CTLA-4, ipilimumab, tremelimumab,                anti-PD-1, anti-PD-L1, anti-PD-L2, anti-KIR, anti-CD137,                or anti-OX40 antibodies, are allowed;            -   (3) Subjects must have received, and then progressed or                been intolerant to, at least one standard treatment                regimen in the advanced or metastatic setting, if such a                therapy exists.        -   ii) Part B Dose Escalation: BMS-986016+BMS-936558            -   (1) All solid tumor histologies are permitted except for                subjects with primary CNS tumors. Subjects with or                without prior anti-PD-1 or anti-PD-L1 antibody therapy                are eligible. Alternatively, all solid tumor histologies                naive to ICMARs such as, but not limited to,                anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2,                anti-KIR, anti-CD137, or anti-OX40 antibodies, will be                permitted except for subjects with primary CNS tumors.            -   (2) Subjects without prior anti-PD-1 or anti-PD-L1                antibody therapy cannot have had prior exposure to any                other ICMARs such as, but not limited to, ipilimumab,                tremelimumab, anti-PD-L2, anti-KIR, anti-CD137, or                anti-OX40 antibodies. Alternatively, Subjects without                prior anti-PD-1 or anti-PD-L1 antibody therapy cannot                have had prior exposure to any other ICMARs such as, but                not limited to, ipilimumab, tremelimumab, anti-PD-L2,                anti-KIR, anti-CD137, or anti-OX40 antibodies.            -   (3) NSCLC subjects whose disease progresses while-on or                after therapy with anti-PD-1 or anti-PD-L1 antibody as                most recent therapy. Alternatively, subjects with prior                anti-PD-1 or anti-PD-L1 antibody as most recent therapy:            -   (a) Disease is nonresponsive while on anti-PD-1 or                anti-PD-L1 antibody therapy and presents with PD (per                RECIST) within 16 weeks of starting therapy.            -   (b) Cannot have had therapy discontinued due to serious                and/or life-threatening anti-PD-1 or anti-PD-L1                antibody-related toxicity (e.g., dose-limiting toxicity                in prior study).            -   (c) Must provide informed consent within 60 days after                the last dose of anti-PD-1 or anti-PD-L1 antibody                therapy.            -   (d) Cannot have had prior exposure to ICMARs such as,                but not limited to, anti-CTLA-4 antibody therapy,                ipilimumab, tremelimumab, anti-PD-L2, anti-KIR,                anti-CD137, or anti-OX40 antibodies.            -   (4) Melanoma subjects whose disease is progressing                while-on or after receiving anti-CTLA-4 and anti-PD-1 or                anti-PD-L1 antibody therapies (a) Anti-CTLA-4 and                anti-PD-1 or anti-PD-L1 antibody therapies could have                been received in sequential or combination regimens (b)                Last dose of anti-CTLA-4 antibody therapy must have been                received ≥100 days of first dose of study medication (c)                Cannot have had therapy discontinued due to serious                and/or life-threatening antibody-related toxicity (e.g.,                dose-limiting toxicity in prior study) (d) Cannot have                had prior exposure to any ICMARs other than anti-CTLA-4                and anti-PD-1 or anti-PD-L1 antibody therapy.            -   (5) Subjects must have received, and then progressed or                been intolerant to at least one standard treatment                regimen.        -   iii) Part C Cohort Expansion            -   (1) The following groups are enrolled:                -   (a) Melanoma—subjects naive to ICMARs                -   (b) Melanoma—subjects whose disease is nonresponsive                    while on anti-PD-1 or anti-PD-L1 antibody therapy as                    most recent therapy and presents with PD (per                    RECIST) within 16 weeks of starting therapy. Subject                    must provide informed consent within 60 days after                    last dose of anti-PD-1 or anti-PD-L1 antibody                    therapy and should have not discontinued antibody                    therapy due to serious and/or life-threatening                    toxicity (e.g., dose-limiting toxicity in prior                    study). These subjects cannot have had prior                    exposure to any other ICMARs such as, but not                    limited to, ipilimumab, tremelimumab, anti-PD-L2,                    anti-KIR, anti-CD137, or anti-OX40 antibodies.                    Alternatively, subjects whose disease is progressing                    while on or after receiving anti-CTLA-4 and                    anti-PD-1 or anti-PD-L1 antibody therapy (in                    sequential or combination regimens), are eligible.                    Last dose of anti-CTLA-4 antibody therapy must have                    been received ≥100 days of first dose of study                    medication. Subjects should have not discontinued                    antibody therapy due to serious and/or                    life-threatening toxicity (e.g., dose-limiting                    toxicity in prior study). These subjects cannot have                    had prior exposure to any ICMARs other than                    anti-CTLA-4 and PD-1 or anti-PD-L1 antibody therapy.                -   (c) Non-small cell lung cancer (NSCLC)—subjects                    naive to ICMARs                -   (d) NSCLC—subjects whose disease is nonresponsive                    while on anti-PD-1 or anti-PD-L1 antibody therapy as                    most recent therapy and presents with PD (per                    RECIST) within 16 weeks of starting therapy. Subject                    must provide informed consent within 60 days after                    last dose of anti-PD-1 or anti-PD-L1 antibody                    therapy and should have not discontinued antibody                    therapy due to serious and/or life-threatening                    toxicity (e.g., dose-limiting toxicity in prior                    study). These subjects cannot have had prior                    exposure to any other ICMARs such as, but not                    limited to, ipilimumab, tremelimumab, anti-PD-L2,                    anti-KIR, anti-CD137, or anti-OX40 antibodies.                    Alternatively, NSCLC subjects whose disease                    progresses while-on or after therapy with anti-PD-1                    or anti-PD-L1 antibody as most recent therapy.                    Subject should have not discontinued antibody                    therapy due to serious and/or life-threatening                    toxicity (e.g., dose-limiting toxicity in prior                    study). These subjects cannot have had prior                    exposure to any other ICMARs such as, but not                    limited to, anti-CTLA-4, anti-PD-L2, anti-KIR,                    anti-CD137, or anti-OX40 antibodies.                -   (e) HPV-associated head and neck tumors—subjects                    naive to ICMARs and with HPV positivity as defined                    by p16 immunohistochemistry (IHC)-positive and/or                    HPV-16 in situ hybridization (ISH)-positive                -    (i) Histology restricted to squamous cell                    carcinoma. Alternatively, subjects with                    advanced/metastatic head and neck tumors naïve to                    ICMARs (i) Histology restricted to squamous cell                    carcinoma.                -   (f) Gastric adenocarcinoma subjects naive to ICMARs                -    (i) HER2(+) and HER2(−) subjects are allowed    -   b) Subjects must have received, and then progressed or been        intolerant to, at least one standard treatment regimen in the        advanced or metastatic setting, if such a therapy exists.    -   c) Subjects with any prior treatment regimens are eligible. The        following are not considered separate lines of treatment:        addition of a compound to an ongoing regimen, restarting the        same regimen after a drug holiday, or switching from IV to oral        therapy.    -   d) Presence of at least one lesion with measurable disease as        defined by RECIST v1.1 criteria for response assessment.        Subjects with lesions in a previously irradiated field as the        sole site of measurable disease are permitted to enroll provided        that the lesion(s) have demonstrated clear progression prior to        the time of informed consent and can be measured accurately.    -   e) ECOG status of 0 or 1.    -   f) Life expectancy of ≥12 weeks at the time of informed consent.    -   g) Adequate organ function as defined by the following:        -   i) White blood cells (WBCs) ≥2000/μL (stable off any growth            factor within 4 weeks of first study drug administration)        -   ii) Neutrophils ≥1500/μL (stable off any growth factor            within 4 weeks of first study drug administration)        -   iii) Platelets ≥100×10³/μL (transfusion to achieve this            level is not permitted within 2 weeks of first study drug            administration)        -   iv) Hemoglobin ≥8.5 g/dL (transfusion to achieve this level            is not permitted within 2 weeks of first study drug            administration)        -   v) Creatinine <1.5×ULN or creatinine clearance ≥40 mL/min            (Cockcroft-Gault formula)        -   vi) ALT and AST≤3×ULN        -   vii) Lipase and amylase <1.5×ULN        -   viii) Total bilirubin ≤1.5×ULN (except subjects with            Gilbert's Syndrome who must have normal direct bilirubin)    -   h) Normal thyroid function, or stable on hormone supplementation    -   i) Ability to comply with treatment, PK, and pharmacodynamic        sample collection and required study follow-up.    -   j) Subject re-enrollment: This study permits the re-enrollment        of a subject that has discontinued the study as a pre-treatment        failure (i.e., subject has not been randomized/has not been        treated). If re-enrolled, the subject must be re-consented.

Age and Reproductive Status

-   -   a) Men and women, ages ≥18 years at the time of informed consent    -   b) Women of childbearing potential (WOCBP) must use methods of        contraception. For a teratogenic study drug and/or when there is        insufficient information to assess teratogenicity (preclinical        studies have not been done), 2 forms of contraception are        required. One method must be highly effective (failure rate of        less than 1% when used consistently and correctly) and the        second method may also be highly effective. The individual        methods of contraception should be determined in consultation        with the Investigator. WOCBP must follow instructions for birth        control for a total of 24 weeks after the last dose of        investigational drug (a period of 30 days plus the time required        for the investigational drug to undergo 5 half-lives). Women of        childbearing potential (WOCBP) are defined as any female who        have experienced menarche and who has not undergone surgical        sterilization (hysterectomy or bilateral oophorectomy) and is        not postmenopausal. Menopause is defined as 12 months of        amenorrhea in a woman over age 45 in the absence of other        biological or physiological causes. In addition, females under        the age of 55 must have a documented serum follicle-stimulating        hormone (FSH) level >40 mIU/mL to confirm menopause. Females        treated with hormone replacement therapy, (HRT) are likely to        have artificially suppressed FSH levels and may require a        washout period in order to obtain a physiologic FSH level. The        duration of the washout period is a function of the type of HRT        used. The duration of the washout period below are suggested        guidelines and the investigators should use their judgement in        checking serum FSH levels. If the serum FSH level is >40 mlU/ml        at any time during the washout period, the woman can be        considered postmenopausal.        -   1 week minimum for vaginal hormonal products, (rings,            creams, gels)        -   4 week minimum for transdermal products        -   8 week minimum for oral products        -   Other parenteral products may require washout periods as            long as 6 months.    -   c) Women must have a negative serum or urine pregnancy test        (minimum sensitivity of urine pregnancy test of 25 IU/L of        either total human chorionic gonadotropin (hCG) or the beta        fraction) within 24 hours prior to the start of investigational        product.    -   d) Women must not be breastfeeding.    -   e) Men who are sexually active with WOCBP must use methods of        contraception. For a teratogenic study drug and/or when there is        insufficient information to assess teratogenicity (preclinical        studies have not been done), 2 forms of contraception are        required. One method must be highly effective (failure rate of        less than 1% when used consistently and correctly) and the        second method may also be highly effective. Men who are sexually        active with WOCBP must follow instructions for birth control for        a total of 33 weeks after the last dose of investigational drug        (a period of 90 days plus the time required for the        investigational drug to undergo 5 half-lives).

Women who are not of childbearing potential (i.e., who arepostmenopausal or surgically sterile; and permanently azoospermic men(e.g., bilateral orchiectomy) do not require contraception. Women ofchildbearing potential (WOCBP) are defined as females who haveexperienced menarche and who have not undergone surgical sterilization(hysterectomy or bilateraloophorectomy) or are not postmenopausal.Menopause is defined clinically as 6 months of amenorrhea in a womanover age 45 in the absence of other biological or physiological causes.In addition, women under the age of 55 must have a documented serumfollicle-stimulating hormone (FSH) level >40 mIU/mL to confirmmenopause.

7. Exclusion Criteria

Target Disease Exceptions

Subjects with known or suspected CNS metastases or with the CNS as theonly site of active disease are excluded with the following exceptions:

-   -   i) Subjects with controlled brain metastases are allowed to        enroll. Controlled brain metastases are defined as those with no        radiographic progression for at least 4 weeks after radiation        and/or surgical treatment at the time of consent. Subjects must        have been off of steroids for at least 2 weeks prior to informed        consent, and have no new or progressive neurological signs and        symptoms.    -   ii) Subjects with signs or symptoms of brain metastases are not        eligible unless brain metastases are ruled out by computed        tomography (CT) or magnetic resonance imaging (MRI).

Participation in any prior clinical study with BMS-936558, includingsubjects in comparator arms, in which overall survival is listed as theprimary or co-primary endpoint and which has not completed analysisbased on the primary endpoint.

Medical History and Concurrent Diseases

Subjects with a prior malignancy are excluded, except adequately treatedbasal cell or squamous cell skin cancer, localized prostate cancer,carcinoma in situ of the cervix or carcinoma in situ of the bladder, orin situ ductal or lobular carcinoma of the breast. Subjects with otherprior malignancies diagnosed more than 2 years previously (at the timeof informed consent) who have received therapy with curative intent withno evidence of disease during the interval who are considered to presenta low risk for recurrence are eligible.

Subjects with any active autoimmune disease or history of known orsuspected autoimmune disease with the exception of subjects withisolated vitiligo, resolved childhood asthma/atopy, controlledhypoadrenalism or hypopituitarism, and euthyroid patients with a historyof Grave's disease (subjects with controlled hyperthyroidism must benegative for thyroglobulin and thyroid peroxidase antibodies andthyroid-stimulating immunoglobulin prior to study drug administration).

A known or underlying medical condition that could make theadministration of study drug hazardous to the subject or could adverselyaffect the ability of the subject to comply with or tolerate study.

Requirement for daily supplemental oxygen.

Uncontrolled or significant cardiovascular disease including, but notlimited to, any of the following: Myocardial infarction orstroke/transient ischemic attack (TIA) within the 6 months prior toconsent, uncontrolled angina within the 3 months prior to consent, anyhistory of clinically significant arrhythmias (such as ventriculartachycardia, ventricular fibrillation, or torsades de pointes), QTcprolongation >480 msec, history of other clinically significant heartdisease (i.e., cardiomyopathy, congestive heart failure with New YorkHeart Association [NYHA] functional classification pericarditis,significant pericardial effusion).

Cardiovascular disease-related requirement for daily supplementaloxygen.

A confirmed history of encephalitis, meningitis, or uncontrolledseizures in the year prior to informed consent.

Positive blood screen for human immunodeficiency virus (HIV) or knownacquired immunodeficiency syndrome (AIDS).

History of any chronic hepatitis as evidenced by positive test forhepatitis A antibody (HepA IgM) (Note: history of resolved hepatitis Avirus infection is not an exclusion criterion), positive test forhepatitis B surface antigen (HBsAg) and/or hepatitis B core antigen,positive test for qualitative hepatitis C viral load (by PCR).

Evidence of active infection that requires systemic antibacterial,antiviral, or antifungal therapy ≤7 days prior to initiation of studydrug therapy.

Any other significant acute or chronic medical illness.

Subjects who are unable to undergo venipuncture and/or tolerate venousacces.

Any other sound medical, psychiatric, and/or social reason.

Any of the following procedures or medications:

Within 2 weeks prior to time of informed consent: systemic or topicalcortico steroids at immunosuppressive doses 7.5 mg/day of prednisone orequivalent), palliative radiation and gamma knife radiosurgery in CNS,or medicinal herbal preparations.

Within 4 weeks prior to study drug administration: any investigationaldrug or placebo, any anticancer therapy (chemotherapy, biologics,therapeutic vaccines, radiotherapy, or hormonal treatment), non-oncologyvaccines containing live virus, allergen hyposensitization therapy,growth factors, e.g., granulocyte-colony stimulating factor (G-CSF),granulocyte macrophage-colony stimulating factor (GM-CSF),erythropoietin, major surgery, or biphosphonates.

Within 10 weeks prior to study drug administration: receptor activatorof nuclear factor kappa-B ligand (RANK-L) inhibitors.

Allergies and Adverse Drug Reaction

History of allergy to anti-PD-1 or anti-PD-L1 antibody therapy or toother monoclonal antibodies or related compounds or to any of theircomponents (e.g., history of severe hypersensitivity reactions to drugsformulated with polysorbate 80).

Other Exclusion Criteria

Prisoners or subjects who are involuntarily incarcerated.

Subjects who are compulsorily detained for treatment of either apsychiatric or physical (e.g., infectious disease) illness.

Inability to comply with restrictions and prohibited activities andtreatments.

8. Guidelines for Dose Modification

Intrasubject dose escalation of BMS-986016 or BMS-936558 is notpermitted in this study. With the possible exception of subjects beingtreated at a dose level that is subsequently deemed to exceed the MTD,intrasubject dose reduction of BMS-986016 or BMS-936558 is notpermitted.

In some cases, the natural history of select adverse events associatedwith immunotherapy can differ from and be more severe than adverseevents caused by other therapeutic classes. Early recognition andmanagement mitigates severe toxicity.

Additionally, management algorithms can assist with select toxicities.Toxicities for which management algorithms have been developed include:

Pulmonary

Gastrointestinal

Hepatic

Endocrine

Renal

Dermatologic

Neurologic

Subjects who experience the following must have all study drug(s) held:

-   -   DLTs (per definition, are related to study drug)    -   Select drug-related adverse events and drug-related laboratory        abnormalities:        -   ≥Grade 1 pneumonitis        -   ≥Grade 2 abnormality in AST, ALT, total bilirubin, amylase,            or lipase        -   ≥Grade 2 creatinine        -   ≥Grade 2 diarrhea or colitis        -   ≥Grade 2 neurological adverse event    -   Adverse event, laboratory abnormality, or concurrent illness        that, in the judgment of the Investigator, warrants delaying the        dose of study drug.

Dose delays >7 days are considered missed and is not be replaced.

9. Safety Assessments

Adverse events are assessed continuously during the study and for 135days after the last treatment. Adverse events are evaluated according tothe NCI CTCAE version 4.0. Adverse events are coded using the mostcurrent version of Medical Dictionary for Regulatory Activities (MedDRA)and reviewed for potential significance and importance.

10. Other Analyses

Various serologic tumor markers, gene mutation status, and additionalanalyses are required dependent upon the subject's tumor type as listedbelow in Table 4. With the exception of the serologic tumor markers, theassessments are not performed if the lab results from previous testingare available.

TABLE 4 Biomarkers by Tumor Type Tumor Type Study Part Matrix Lab TestAssessment Timepoint Colorectal Parts A, B Blood Serologic Tumor CEA^(a)Multiple ONLY Marker Parts A, B Tumor Gene Mutation EGFR^(b) ScreeningONLY Tissue Status K-RAS MSI^(c) Gastric Parts A, B, C Blood SerologicTumor CEA^(a) Multiple Marker Parts A, B, C Tumor Gene MutationHER-2^(d) Screening Tissue Status Parts A, B, C Tumor Real Time EBV^(f)Screening Tissue qPCR^(e) Germ Cell Parts A, B Blood Serologic TumorβhCG^(g) Multiple ONLY Marker AFP^(h) Head and Part C ONLY Tumor IHCand/or ISH^(i) HPV^(j) Screening Neck Tissue (Eligibility) MelanomaParts A, B, C Tumor Gene Mutation BRAF Screening Tissue Status NSCLCParts A, B, C Tumor Gene Mutation ALK^(k) Screening Tissue Status K-RASEGFR^(b) Ovarian Parts A, B Blood Serologic Tumor CA125^(l) MultipleONLY Marker Prostate Parts A, B Blood Serologic Tumor PSA^(m) MultipleONLY Marker ^(a)CEA: carcinoembryonic antigen ^(b)EGFR: epidermal growthfactor receptor ^(c)MSI: microsatellite instability ^(d)HER-2: humanepidermal growth factor receptor 2 status via IHC and/or ISH ^(e)Realtime qPCR: real time quantitative polymerase chain reaction for BamH1-AReading Frame-1(BARF1) gene ^(f)EBV: Epstein-Barr virus ^(g)βhCG:beta-human chorionic gonadotrophin ^(h)AFP: alpha-fetoprotein ^(i)IHCand/or ISH: p16 immunohistochemistry (IHC) and/or HPV-16 in situhybridization (ISH) ^(j)HPV: human papilloma virus ^(k)ALK: anaplasticlymphoma kinase ^(l)CA125: cancer antigen 125 ^(m)PSA: prostate specificantigen

Additional measures, including non-study-required laboratory tests, areperformed as clinically indicated. Results of all laboratory testsrequired by this protocol are recorded.

11. Efficacy Assessments

Efficacy is evaluated in Parts A and B (dose escalation), as well as inPart C (cohort expansion). Changes in tumor measurements and tumorresponse at the time of each assessment are determined. The baselineassessment during the screening period requires CT or MRI scans of thechest, abdomen, and pelvis, and other anatomic regions as indicated byindividual subject's tumor type and/or disease history. Subsequenttimepoints require scans of the chest, abdomen, and pelvis, as well asother anatomic regions that were scanned at baseline based on theindividual subject's tumor type and/or disease history. Scans of thebrain are otherwise required as clinically indicated.

Analysis of response endpoints are performed according to immune-relatedresponse criteria, irRECIST that reflect the clinical experience withother T cell-directed immunotherapies in which objective and durableresponses were observed in subjects following progression and withoutintervening alternative anticancer therapy (Wolchok J D, et al., Clin.Can. Res. 2009; 15(23):7412-7420). Individual subject's best overallresponse (BOR), duration of progression-free survival (PFS), andduration of response (DOR) is calculated as appropriate.

Tumor status are assessed at baseline, during treatment (every 8 weeks)for up to twelve 8-week cycles of therapy, and once during follow-up. CTand MRI scans re read and assessed locally per RECIST v1.1. All imagingscans are de-identified and archived in their native Digital Imaging andCommunications in Medicine (DICOM) format as part of the subject's studyfile.

The efficacy assessments include the ORR (e.g., PR+CR), DOR, and PFSR atlandmark timepoints (e.g., 24 weeks), based on assessment of tumorresponse using irRECIST and RECIST v1.1. Landmark 2-year overallsurvival (OS).

12. Pharmacokinetic Assessments

Serum samples for BMS-986016 pharmacokinetics and anti-drug antibody(ADA) assessments are collected for all subjects. Serum samples forBMS-936558 pharmacokinetics and ADA assessments re collected for allsubjects enrolled in Part B and C. The serum samples are analyzed forBMS-986016 and BMS-936558 by a validated immunoassay. In addition,selected serum samples are analyzed by an exploratory orthogonal method(e.g., liquid chromatography [LC]-mass spectrometry [MS]/MS) thatmeasures total BMS-986016 and/or BMS-936558.

13. Exploratory Biomarker Assessment

The pharmacodynamics of BMS-986016 treatment administered alone or incombination with BMS-936558 is assessed by quantifying biomarkers inperipheral blood and tumor tissue in the first 3 subjects enrolled ateach dose level during the dose escalation (Parts A and B) and insubjects with melanoma and head and neck cancers during cohort expansion(Part C) phases of the study. Detailed schedules of pharmacodynamicevaluations are provided below in Tables 5-6. Details regarding thetumor tissues requirements for subjects in Parts A, B, and C of thestudy are provided below in Table 7.

TABLE 5A Part A & B (Dose Escalation) - Biomarker Sampling Schedule(ONLY for First 3 Subjects in each Dose Level) PBMC Collection SerumImmunophenotyping/ Ex vivo Tumor Whole Blood Timing Soluble BiomarkersTetramer Functional Assay Archival Gene Expression Study Day (SerumBiomarkers) (Flow Cytometry/PBMC) (Cellular Assay) Tissue^(a) (WholeBlood mRNA) SNP Screening X Cycle 1 Day 1 X X X X X Day 5^(a) X Day 8 XX Day 15 X X X Day 29 X X X Day 43 X X X X Cycle 2 Day 29 X X X X UponProgression Upon X X X X X Progression^(b) ^(a)Day 5 visit can occur onDay 3 or Day 4 ^(b)Optional; collected upon confirmation of PD NOTE: Allsamples are drawn pre-dose

TABLE 5B Part A & B (Dose Escalation) - Biomarker Sampling Schedule(ONLY for First 3 Subjects in each Dose Level) PBMC Collection SerumImmunophenotyping/ Ex vivo Tumor Whole Blood Timing Soluble BiomarkersTetramer Functional Assay Archival Gene Expression Study Day (SerumBiomarkers) (Flow Cytometry/PBMC) (Cellular Assay) Tissue (Whole BloodmRNA) SNP Screening X Cycle 1 Day 1 X X X X X Day 5^(b) X Day 8 X X Day15 X X X Day 29 X X X Day 43 X X X X Cycle 2 Day 29 X X X X UponProgression Upon X X X X X Progression^(b) Upon Drug-related AE Upon X XX occurrence of ≥Grade 2 drug related pneumonitis or neurological AE aDay 5 visit can occur on Day 3 or Day 4. Day 8 visit can occur on Day 7or Day 9. ^(b)Optional; collected upon confirmation of PD NOTE: Allsamples are drawn pre-dose

TABLE 6A Part C (Cohort Expansion) - Biomarker Sampling Schedule (ONLYfor Subjects with Melanoma and Head and Neck Cancer) PBMC CollectionSerum Immunophenotyping/ Ex vivo Tumor Whole Blood Timing SolubleBiomarkers Tetramer Functional Assay “Fresh” Gene Expression Study Day(Serum Biomarkers) (Flow Cytometry/PBMC) (Cellular Assay) Tumor Biopsy(Whole Blood mRNA) SNP Screening X^(a) Cycle 1 Day 1  X^(b) X X X X Day5^(c) X Day 8 X X Day 15 X X X Day 29 X X X Day 43 X X X X Day 50-56X^(d) Cycle 2 Day 29 X X X X Upon Progression Upon X X X X  XProgression^(e) NOTE: All samples are drawn pre-dose ^(a)Fresh tumorbiopsy is mandatory for subjects with melanoma and head and neck cancerin Part C. ^(b)Serum and plasma at Cycle 1 Day 1. Serum only at allother timepoints. ^(c)Day 5 visit can occur on Day 3 or Day 4 ^(d)Freshtumor biopsy is mandatory for subjects with melanoma and head and neckcancer in Part C. Biopsy is obtained at anytime during Cycle 1, Week 8(Days 50-56) at the same time as diagnostic imaging. ^(e)Optional;collected upon confirmation of PD

TABLE 6B Part C (Cohort Expansion) - Biomarker Sampling Schedule (ONLYfor Subjects with Melanoma and Head and Neck Cancer) PBMC^(b) CollectionSerum Plasma Immunophenotyping/ Ex vivo Tumor Whole Blood Timing Soluble(Serum Tetramer (Flow Functional Assay “Fresh” Gene Expression Study DayBiomarkers Biomarkers) Cytometry/PBMC) (Cellular Assay) Tumor Biopsy(Whole Blood mRNA) SNP Screening X^(a) Cycle 1 Day 1 X X X X X X Day5^(c) X Day 8^(c) X X Day 15 X X X Day 29 X X X X Day 36 X X X Day 43 XX X X X Day 50-56 X^(d) Cycle 2 Day 29 X X X X Upon Progression Upon X XX X  X Progression^(c) Upon Drug-related AE Upon X X X occurrence of≥Grade 2 drug related pneumonitis or neurological AE ^(a)Fresh tumorbiopsy is mandatory for subjects with melanoma and head and neck cancerPart C. ^(b)PBMC samples only to be collected for subjects in the US,not required for subjects Ex-US. ^(c) Day 5 visit can occur on Day 3 orDay 4. Day 8 visit can occur on Day 7 or Day 9. ^(d)Fresh tumor biopsyis mandatory for subjects with melanoma and head and neck cancer in PartC. Biopsy can be obtained at anytime during Cycle 1, Week 8 (Days 50-56)at same time as diagnostic imaging. e Optional; to be collected uponconfirmation of PD.

TABLE 7 Tumor Tissue Requirements for Parts A, B, and C Part A and BPart C Study Part (Dose Escalation) (Cohort Expansion) Subjects ALLsubjects in Part A Subjects with Subjects with or B melanoma or head andNSCLC or gastric neck tumors adenocarcinoma ONLY ONLY Type of Archivedtumor tissue. Mandatory “fresh” Archived tumor Specimen If archivedsample is not biopsies (pre- and on- tissue. available, must obtain atreatment) If archived “fresh” pre-treatment sample is not tumor biopsyavailable, must obtain a “fresh” pre-treatment tumor biopsy UponOptional “fresh” biopsy Optional “fresh” biopsy Optional “fresh”Progression upon confirmation of upon confirmation of biopsy upon PD PDconfirmation of PD

Soluble Biomarkers (Serum Biomarkers)—Parts A, B, and C

Pre-treatment and on-treatment serum levels of chemokines, cytokines,and tumor-associated soluble proteins is assessed by techniques thatinclude, but are not limited to, ELISA or multiplex assays. Analytesinclude markers of inflammation, immune activation, host tumor growthfactors, and tumor-derived proteins.

Antitumor Antibodies (Serum Biomarkers)—Parts A, B, and C

Treatment with BMS-986016 and BMS-936558 may result in the generation ofnovel, or an increase in existing, antibodies to tumor-associatedantigens. An assessment of antibodies to a panel of >8000 proteins isperformed using pre-treatment and on-treatment serum in multiplex andELISAs. These data are used to explore if antitumor antibodies areassociated with clinical response and safety parameters, as well asinform pharmacodynamics of drug administration.

Immunophenotyping (Flow Cytometry/PBMC)—Parts A, B, and C

Peripheral blood mononuclear cells (PBMCs) are used to characterize andquantify the activation and regulatory status of myeloid and lymphoidcells by polychromatic flow cytometry. Subsets of cells characterized byimmunophenotyping include naive, activated, and exhausted effector andmemory T cell populations, regulatory T cells, and myeloid-derivedsuppressor cells.

Ex Vivo Functional Assays (Cellular Assay)—Parts A, B, and C

To assess whether BMS-986016 and BMS-936558 restores T cell activationand function, PBMCs are isolated and cryopreserved. The functionalstatus of effector T cells, including, but not limited to, IFN-γ andgranzyme B, is assessed by flow cytometric staining.

Peripheral Blood Gene Expression (Whole Blood mRNA) and Tumor GeneExpression—Parts A, B, and C

The expression level of genes related to response toBMS-986016±BMS-936558 is quantified by microarray and/or quantitativereverse transcription polymerase chain reaction (RT-PCR) analysis inwhole blood and tumor samples. Analysis includes, but is not necessarilybe limited to, genes encoding BMS-986016-stimulated effector functions(perforin, granzyme B, and IFN-γ) and genes encoding T cellco-stimulatory receptors (PD-1, PD-L1, and CTLA-4).

Circulating Tumor DNA Analysis (Serum (Plasma) Biomarkers)—Part C

The presence of cell-free DNA in circulating blood is a well-documentedphenomenon. Fragments of DNA are shed into the blood stream fromdividing cells during cell proliferation or cell death. In patients withcancer, a fraction of this DNA is tumor-derived and is termedcirculating tumor DNA (ctDNA). Albeit small, fragments of DNA averagebetween 180 to 200 bp and specific genomic regions can be amplified withPCR. Moreover, several studies have detected mutations in ctDNA thatexactly correspond to mutations from the parent tumor. Using tissue andplasma from patients with known driver mutations in melanoma or head andneck cancer, BEAMing technology is utilized to count the frequency ofmutations in circulation.

Single Nucleotide Polymorphism Analysis (SNP)—Parts A, B, and C

In order to identify potential polymorphisms associated with the safetyand efficacy of BMS-986016 selected genes are evaluated for singlenucleotide polymorphisms (SNPs). Genes of interest include, but are notlimited to, PD-1, PD-L1, MHC class II, LAG-3, and CTLA-4.

Tumor Biopsy Analysis—Parts A and B

Tumor tissue is collected from all subjects in the dose escalationportion of the protocol. Immunohistochemistry is used to assess thenumber and composition of immune infiltrates to define the immune cellsubsets present within FFPE tumor tissue before and potentially afterexposure to BMS-986016 and BMS-936558. These IHC analyses include, butare not necessarily be limited to, the following markers: CD4, CD8,LAG-3, MHC II, PD-1, PD-L1, and PD-L2. Correlations between geneexpression and IHC expression are made between assays performed ifdeemed to be informative.

Tumor-Based Biomarker Measures—Part C

Paired pre- and on-treatment tumor biopsies are mandatory for allsubjects with melanoma or head and neck cancer who are enrolled in PartC (cohort expansion). Subjects for whom adequate paired pre- andon-treatment biopsies are not collected may be replaced.

Subjects have at least one lesion large enough to undergo repeatedbiopsies (pre- and on-treatment biopsies) via core needle (minimum size18 gauge) or have at least 2 distinct lesions eligible for core needleor excisional biopsies. The expected core needle length should begreater than 5 mm. A punch biopsy is acceptable for cutaneous lesions.Fine needle aspirate biopsies are not accepted. At least two corebiopsies are taken at each timepoint, but collection of additional coresis strongly encouraged if deemed clinically safe by the investigator. Anassessment of biopsy quality by a pathologist is strongly encouraged atthe time of the procedure. All biopsies collected must have a detailedpathology report submitted with the specimen.

Tumor biopsy specimens are obtained from consenting subjects prior toand during treatment with BMS-986016 and BMS-936558 to characterizeimmune cell populations and expression of selected tumor markers. Biopsysamples are used for the following assessments:

-   -   Characterization of TILs and tumor antigens.        Immunohistochemistry is used to assess the number and        composition of immune infiltrates to define the immune cell        subsets present within FFPE tumor tissue before and after        exposure to BMS-986016 and nivolumab. These IHC analyses        include, but are not necessarily limited to, the following        markers: CD4, CD8, LAG-3, MHC II, PD-1, PD-L1, and PD-L2.        Correlations between gene expression and IHC expression are made        between assays performed if deemed to be informative.    -   Laser capture microdissection. Isolation of tumor and/or TIL on        FFPE sections is performed by laser capture microdissection        (LCM) for high-throughput profiling of molecular events within        the tumor microenvironment.    -   Characterization of T cell repertoire. DNA sequencing is        performed on pre- and post-treatment FFPE tumor tissue to assess        the composition of the T cell repertoire. Low T cell receptor        diversity may be a poor prognostic factor of overall survival in        metastatic breast cancer patients. Currently, there is a poor        understanding of T cell receptor diversity as a predictor factor        of response to immunotherapy, given that the major mechanism of        BMS-936558 and BMS-986016 is hypothesized to be the functional        restoration of T cell antitumor immunity. Therefore, a        characterization of the diversity of the T cell compartment in        the periphery, and within the tumor, at baseline and        on-treatment is performed by T cell receptor next-generation DNA        sequencing. T cell repertoire analysis is also performed from        DNA isolated from peripheral blood to compare the status of        tumor and peripheral T cell repertoire pre and post treatment.    -   Gene expression profiling. Tumor biopsies that are collected in        RNAlater or similar reagent are examined for mRNA gene        expression by Affymetrix gene array technology and/or        quantitative real-time polymerase chain reaction (qPCR) to        detect expression of selected immune-related genes.    -   In situ cytokine and negative regulator expression. Tumors        biopsies are quantitatively evaluated for RNA, including CD3,        IFN-γ, LAG-3, and PD-1.

Subjects whose screening biopsy yields inadequate tissue quantity orquality are allowed to continue in the study. If on-treatment biopsy isnot successful, subjects also continue on study. Such subjects arereplaced in order to obtain 48 subjects with adequate paired tumorbiopsies. If subjects have a response to treatment, on-treatmentbiopsies might not be possible. In this case, subjects also continue onstudy.

The tumor tissue that is obtained from these biopsies is divided equallyinto FFPE and frozen samples, which can be used for histologicconfirmation of melanoma, as well as for the assays listed above.

Biopsies are done with local anesthesia or conscious sedation.Institutional guidelines for the safe performance of biopsies arefollowed. Excisional biopsies are performed to obtain tumor biopsysamples. Invasive procedures that require general anesthesia are notperformed to obtain a biopsy specimen. However, if a surgical procedureis performed for a clinical indication, excess tumor tissue is used forresearch purposes with the consent of the subject.

14. Immunogenicity Assessments

Serum samples collected at timepoints are analyzed by a validatedimmunogenicity assay. Selected serum samples are analyzed by anexploratory orthogonal method that measures anti-BMS-986016 oranti-BMS-936558. Potential results generated from any orthogonal methodare intended as informational for technology exploration purposes and renot reported.

In addition, ad hoc serum samples designated for pharmacokinetic orbiomarker assessments are used for immunogenicity analysis if required(e.g., insufficient volume for complete immunogenicity assessment or tofollow up on suspected immunogenicity related adverse event).

15. Adverse Events

An adverse event (AE) is defined as any new untoward medical occurrenceor worsening of a preexisting medical condition in a clinicalinvestigation subject administered an investigational (medicinal)product and that does not necessarily have a causal relationship withthis treatment. An AE is therefore any unfavorable and unintended sign(such as an abnormal laboratory finding), symptom, or disease temporallyassociated with the use of investigational product, whether or notconsidered related to the investigational product.

The causal relationship to study drug is determined by a physician andused to assess all adverse events (AE). The casual relationship can beone of the following:

-   -   Related: There is a reasonable causal relationship between study        drug administration and the AE.    -   Not related: There is not a reasonable causal relationship        between study drug administration and the AE.

The term “reasonable causal relationship” means there is evidence tosuggest a causal relationship.

Serious Adverse Events

A serious adverse event (SAE) is any untoward medical occurrence that atany dose:

-   -   results in death    -   is life-threatening (defined as an event in which the subject        was at risk of death at the time of the event; it does not refer        to an event which hypothetically might have caused death if it        were more severe)    -   requires inpatient hospitalization or causes prolongation of        existing hospitalization    -   results in persistent or significant disability/incapacity    -   is a congenital anomaly/birth defect    -   is an important medical event (defined as a medical event(s)        that may not be immediately life-threatening or result in death        or hospitalization but, based upon appropriate medical and        scientific judgment, may jeopardize the subject or may require        intervention (e.g., medical, surgical) to prevent one of the        other serious outcomes listed in the definition above). Examples        of such events include, but are not limited to, intensive        treatment in an emergency room or at home for allergic        bronchospasm; blood dyscrasias or convulsions that do not result        in hospitalization.) Potential drug induced liver injury (DILI)        is also considered an important medical event.

Suspected transmission of an infectious agent (e.g., pathogenic ornonpathogenic) via the study drug is an SAE. Although pregnancy,overdose, cancer, and potential drug induced liver injury (DILI) are notalways serious by regulatory definition, these events must be handled asSAEs. Any component of a study endpoint that is considered related tostudy therapy (e.g., death is an endpoint, if death occurred due toanaphylaxis, anaphylaxis must be reported) is reported as SAE.

The following hospitalizations are not considered SAEs:

-   -   a visit to the emergency room or other hospital department <24        hours, that does not result in admission (unless considered an        important medical or life-threatening event)    -   elective surgery, planned prior to signing consent    -   admissions as per protocol for a planned medical/surgical        procedure    -   routine health assessment requiring admission for        baseline/trending of health status (e.g., routine colonoscopy)    -   medical/surgical admission other than to remedy ill health and        planned prior to entry into the study. Appropriate documentation        is required in these cases    -   admission encountered for another life circumstance that carries        no bearing on health status and requires no medical/surgical        intervention (e.g., lack of housing, economic inadequacy,        caregiver respite, family circumstances, administrative reason).

Following the subject's written consent to participate in the study, allSAEs, whether related or not related to study drug, are collected,including those thought to be associated with protocol-specifiedprocedures. All SAEs are collected that occur during the screeningperiod and within 135 days of discontinuation of dosing. If applicable,SAEs are collected that relate to any later protocol-specified procedure(e.g., a follow-up skin biopsy). All SAEs are followed to resolution orstabilization.

Nonserious Adverse Events

A nonserious adverse event is an AE not classified as serious. Thecollection of nonserious AE information begins at initiation of studydrug and continues for 135 days after discontinuation of dosing.Nonserious AEs are followed to resolution or stabilization, or reportedas SAEs if they become serious. Follow-up is also required fornonserious AEs that cause interruption or discontinuation of study drugand for those present at the end of study treatment as appropriate. Allidentified nonserious AEs are recorded and described on the nonseriousAE page of the CRF (paper or electronic).

Completion of supplemental CRFs are requested for AEs and/or laboratoryabnormalities that are reported/identified during the course of thestudy.

16. Statistical Considerations

Sample Size Determination

Dose Escalation (Parts A and B): Sample size at each dose depends onobserved toxicity and cannot be precisely determined. Part A and Part Bhave 3 to 9 subjects in each cohort.

Cohort Expansion (Part C): Cohort expansion allows for better estimationof the toxicity rate and provide better precision around preliminaryestimates of efficacy. If ≤5 of 16 subjects (i.e., ˜30% of in a cohort)experience a toxicity, there is at least 90% confidence that the truetoxicity rate is not greater than 50.4% (based on Clopper-Pearson exactbinomial 1-sided 90% confidence interval). A sample size of 16 subjectsper cohort also allows for estimation of the proportion of subjects withobjective response (i.e., CR+PR) within a cohort such that the maximumdistance between the estimated rate and either limit of the exact2-sided 95% Clopper-Pearson confidence interval is 27.4%.

Populations for Analyses

-   -   All Enrolled Subjects Analysis Set: This analysis set contains        all subjects (including screen failures) who signed an informed        consent for the study.    -   All Treated Subjects-Analysis set: This analysis set includes        all subjects who receive either drug.    -   Response-Evaluable Subjects: This analysis set includes all        subjects who receive either study drug, have a baseline tumor        assessment with measurable disease, and one of the        following: (1) at least one evaluable on-treatment tumor        assessment, (2) clinical progression, or (3) death prior to the        first on-treatment tumor evaluation.    -   BMS-986016 Pharmacokinetic Analysis Set: This analysis set        includes all subjects who receive BMS-986016 and have at least        one valid PK parameter to be included in statistical analyses of        BMS-986016 PK data.    -   BMS-986016 Immunogenicity Analysis Set: This analysis set        includes all subjects who receive BMS-986016 and have at least        one BMS-986016 immunogenicity sample available.    -   BMS-936558 Immunogenicity Analysis Set: This analysis set        includes all subjects who receive BMS-936558 and have at least        one BMS-936558 immunogenicity sample available.    -   Pharmacodynamic Analysis Set: This analysis set includes all        treated subjects for whom pharmacodynamic measurements are        available at baseline and at least one other timepoint.

Endpoints

The primary endpoint of this Phase 1 study is safety as measured by therate of AEs, serious adverse events (SAEs), deaths, and laboratoryabnormalities (e.g., Grade 3 or higher per CTCAE v 4), assessed duringtreatment and for up to 135 days of follow-up. All subjects who receiveat least one dose of BMS-986016 or BMS-936558 are analyzed for safety.

The PK of BMS-986016 administered both alone and in combination withBMS-936558 is assessed as a secondary objective using the followingendpoints derived from serum concentration versus time data in Cycle 1and Cycle 3:

-   Cmax Maximum observed serum concentration-   Tmax Time of maximum observed serum concentration-   Ctrough Trough observed serum concentration-   Ctau Concentration at the end of a dosing interval (e.g.,    concentration at 336 hours)-   Css,avg Average concentration over a dosing interval ([AUC(TAU)/tau]-   AUC(TAU) Area under the concentration-time curve in one dosing    interval-   CLT Total body clearance-   Vss Volume of distribution at steady state-   T-HALFeff AUC Effective elimination half-life that explains the    degree of AUC accumulation observed-   T-HALFeff Cmax Effective elimination half-life that explains the    degree of Cmax accumulation observed-   AI_AUC Accumulation index; ration of AUC(TAU) at steady state to    AUC(TAU) after the first dose-   AI_CMAS Cmax accumulation index; ratio of Cmax at steady state to    Cmax after the first dose-   AI_Ctau Ctau accumulation index; ratio of Ctau at steady state to    Ctau after the first dose-   DF Degree of fluctuation or fluctuation index ([Cmax −Ctau]/Css,avg)

Individual subject PK parameter values are derived by noncompartmentalmethods by a validated PK analysis program. Actual times are used forthe analyses.

Efficacy

Efficacy is assessed as a secondary objective using the endpointsdescribed below for irRECIST and RECIST v1.1. For the purposes ofpatient management, clinical decision making is based on RECIST.Statistical analysis and reporting are based on both criteria.

-   -   Best overall response (BOR) is the best response designation        recorded from the start of the study treatment until the last        protocol specified tumor assessment (e.g., 30 day follow-up        visit) taking into account any requirement for confirmation,        based on RECIST v1.1 or irRECIST criteria. CR or PR        determinations included in the BOR assessment are confirmed by a        consecutive second (confirmatory) evaluation meeting the        criteria for response and performed at least 4 weeks after the        criteria for response are first met.    -   Objective response rate (ORR) is defined as the total number of        subjects whose BOR is either CR or PR divided by the total        number of subjects in the population of interest.    -   Duration of response (DOR) computed only for subjects with a BOR        of CR or PR is defined as the number of days between the date of        first response and the subsequent date of objectively documented        disease progression based on the criteria (RECIST v1.1 or        irRECIST) or death, whichever occurs first. For those subjects        who remain alive and have not progressed or received subsequent        therapy, duration of response is censored on the date of last        protocol specified tumor assessment. Subjects who receive        subsequent therapy are censored at the start of subsequent        therapy.    -   Progression free survival (PFS) is defined as the probability of        a subject remaining progression-free and surviving. The        probability is computed based on the number of days between the        first dose of study drug and progressive disease (as defined by        RECIST or irRECIST) or death. For those subjects who remain        alive and have not progressed, PFS is censored on the date of        the last protocol specified tumor assessment.

These endpoints are determined based on tumor measurements occurringevery 8 weeks during the Treatment Period (up to twelve 8-week cycles),and once during the Clinical Follow-up period (30 days), for a total of˜1.9 years.

Immunogenicity

At the sample level, individual samples are characterized asADA-positive or ADA-negative. A subject is considered to have a positivesample at baseline if the last sample prior to the initiation oftreatment is ADA-positive. For example, a post-baseline sample from asubject who is ADA-negative at baseline is considered ADA-positive ifADA is detected. A post-baseline sample from a subject who isADA-positive at baseline is considered ADA-positive if there is arelevant increase in titer (magnitude of the increase in titerconsidered relevant may vary by drug and assay, and is delineated in thestatistical analysis plan). At the subject level, relevant ADA endpointsmay include:

-   -   Proportion of subjects with an ADA-positive sample at baseline    -   Proportion of ADA-positive subjects (on treatment and overall)    -   Proportion of subjects who are persistently positive (e.g., 2 or        more sequential ADA-positive samples with an adequate elapse of        time in-between)    -   Proportion of subjects who have neutralizing antibodies detected        in one or more samples

Centrally Read ECGs (Parts A and B)

In Part A and Part B, QTc is assessed by a central reader at follow-upvisit 1, and on day 1 of Cycle 1 and Cycle 3 (pre-dose and 4 hourpost-dose time points). These assessments are used to address thesecondary objective of assessing the effect of BMS-986016 administeredalone and in combination with BMS-936558 on QTc. ECGs assessed locallyby the investigator are also collected at the start of each cycle.

Biomarker Endpoints

Biomarker endpoints from peripheral blood are generally measured atmultiple timepoints, and evaluated as both predictive andpharmacodynamic markers in the context of the exploratory biomarkerobjectives. These may include measures such as levels and change frombaseline in levels of the following at each scheduled timepoint:

-   -   Serum soluble factors    -   The proportion of specific lymphocyte subsets/expression levels        of T cell co-stimulatory markers assessed using flow cytometry    -   Expression of genes encoding BMS-986016—stimulated effector        functions (perforin, granzyme B, and IFN-γ) and genes encoding T        cell co-stimulatory receptors (PD-1, PD-L1, and CTLA-4).    -   Percent of subjects expressing single nucleotide polymorphisms        linked to PD-1 genes (per SNP)    -   Measures of the quantity and diversity of antibodies observed to        tumor-associated antigens (Part C only)

Biomarker endpoints from tumor biopsies are explored predominantly in aneffort to identify baseline markers predictive of efficacy, since theyare only measured at baseline for most subjects. For the subset ofsubjects who have both pre-treatment and on-treatment biopsies,pharmacodynamic associations are explored. Endpoints may includemeasures, such as pre-treatment levels and change in levels observedon-treatment of:

-   -   Functional status of lymphocytes measured as the percent of CD8+        T-cells positive for IFN-γ and granzyme B expression, and the        geometric mean intensity (log-scale) of CD8+ cells that are        positive for IFN-γ and granzyme B expression (via ex vivo        functional assay)    -   Expression of genes encoding BMS-986016-stimulated effector        functions (perforin, granzyme B, and IFN-γ) and genes encoding T        cell co-stimulatory receptors (PD-1, PD-L1, and CTLA-4)    -   IHC assessment of the presence/absence and intensity (measured        using a discrete scale: such as 0, 1, 2, 3, 4) of expression of        LAG-3, MHC class II, PD-1, PD-L1, and PD-L2.

Appropriate functional transformation of these exploratory measures areapplied as necessary.

Pharmacokinetics

BMS-936558 concentration-time data at scheduled trough (Ctrough) andend-of-infusion timepoints is evaluated as an exploratory endpoint.Measurements are collected on treatment (up to 12 cycles) and for up to135 days during the post-treatment follow-up.

PK parameters for BMS-986016 are calculated using noncompartmentalanalyses. Summary statistics are tabulated for the PK parameters ofBMS-986016 by dose and study day/cycle. To describe the association ofthese parameters with dose of BMS-986016, scatter plots of Cmax andAUC(TAU) versus dose are provided for each day/cycle measured. Doseproportionality of BMS-986016 when administered alone or co-administeredwith BMS-936558 is also assessed based on a power model. Troughconcentrations of BMS-986016 re plotted versus study day and cycle.BMS-936558 end-of-infusion and trough (Ctrough) concentrations aretabulated using summary statistics.

SEQUENCE SUMMARY SEQ ID NO: SEQUENCE  1 Heavy Chain Amino Acid SequenceAnti-LAG-3 mAb (BMS-986016)(variable region underlined; constant region bold)QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYS DYEYNWFDPWGQGTLVTVSSASTKGPSVPPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK*  2Light Chain Amino Acid Sequence Anti-LAC-3 mAb (BMS-986016)(variable region underlined; constant region bold)EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQ GTNLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQG LSSPVTKSFNRGEC*  3Heavy Chain Variable Region (VH) Amino Acid SequenceAnti-LAG-3 mAb (BMS-986016)QVQLQQWGAGLLKPSETLSLTCAVYGGSFSDYYWNWIRQPPGKGLEWIGEINHRGSTNSNPSLKSRVTLSLDTSKNQFSLKLRSVTAADTAVYYCAFGYSDYEYNWFDPWGQGTLVTVSS  4Heavy Chain Variable Region (VH) Nucleotide SequenceAnti-LAG-3 mAb (BMS-986016)caggtgcagctacagcagtggggcgcaggactgttgaagccttcggagaccctgtccctcacctgcgctgtctatggtgggtccttcagtgattactactggaactggatccgccagcccccagggaaggggctggagtggattggggaaatcaatcatcgtggaagcaccaactccaacccgtccctcaagagtcgagtcaccctatcactagacacgtccaagaaccagttctccctgaagctgaggtctgtgaccgccgcggacacggctgtgtattactgtgcgtttggatatagtgactacgagtacaactggttcgacccctggggccagggaaccctggtcaccgtctcctca  5Light Chain Variable Region (VL) Amino Acid SequenceAnti-LAG-3 mAb (BMS-986016)EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGQ GTNLEIK  6Light Chain Variable Region (VL) Nucleotide SequenceAnti-LAG-3 mAb (BMS-986016)gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtattagcagctacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctatgatgcatccaacagggccactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattactgtcagcagcgtagcaactggcctctcacttttggccaggggaccaacctggagatc aaa  7Heavy Chain CDR1 Amino Acid Sequence Anti-LAG-3 mAb (BMS-986016) DYYWN 8 Heavy Chain CDR2 Amino Acid Sequence Anti-LAG-3 mAb (BMS-986016)EINHRGSTNSNPSLKS  9 Heavy Chain CDR3 Amino Acid SequenceAnti-LAG-3 mAb (BMS-986016) GYSDYEYNWFDP 10Light Chain CDR1 Amino Acid Sequence Anti-LAG-3 mAb (BMS-986016)RASQSISSYLA 11 Light Chain CDR2 Amino Acid SequenceAnti-LAG-3 mAb (BMS-986016) DASNRAT 12Light Chain CDR3 Amino Acid Sequence Anti-LAG-3 mAb (BMS-986016)QQRSNWPLT 13 Human LAG-3 Amino Acid SequenceMWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLRASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWGCILTYRDGFNVSIMYNLTVLGLEPPTPLIVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLTLGVLSLLLLVTGAFGFHLWRRQWRPRRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL* 14 LAG-3 EpitopePGHPLAPG 15 LAG-3 Epitope HPAAPSSW 16 LAG-3 Epitope PAAPSSWG 17Heavy Chain Amino Acid SequenceAnti-PD-1 mAb (BM5936558; 5C4 in WO 2006/121168)(variable region underlined; constant region bold)QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDT AVYYCATNDDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAA LGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK 18 Light Chain Amino Acid SequenceAnti-PD-1 mAb (BM5936558; 5C4 in WO 2006/121168)(variable region underlined; constant region bold)EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPR TFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC19 Heavy Chain Variable Region (VH) Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 4 from WO 2006/121168)QVQLVESGGGVVQPGRSLRLDCKASGITFSNSGMHWVRQAPGKGLEWVAVIWYDGSKRYYADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCATND DYWGQGTLVTVSS 20Heavy Chain Variable Region (VH) Nucleotide SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 60 from WO 2006/121168)cag gtg cag ctg gtg gag tct ggg gga ggc gtg gtc cag cct gggagg tcc ctg aga ctc gac tgt aaa gcg tct gga atc acc ttc agtaac tct ggc atg cac tgg gtc cgc cag gct cca ggc aag ggg ctggag tgg gtg gca gtt att tgg tat gat gga agt aaa aga tac tatgca gac tcc gtg aag ggc cga ttc acc atc tcc aga gac aat tccaag aac acg ctg ttt ctg caa atg aac agc ctg aga gcc gag gacacg gct gtg tat tac tgt gcg aca aac gac gac tac tgg ggc caggga acc ctg gtc acc gtc tcc tca 21Light Chain Variable Region (VL) Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 11 from WO 2006/121168)EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSSNWPRTFGQ GTKVEIK 22Light Chain Variable Region (VL) Nucleotide SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 67 from WO 2006/121168)gaa att gtg ttg aca cag tct cca gcc acc ctg tct ttg tct ccaggg gaa aga gcc acc ctc tcc tgc agg gcc agt cag agt gtt agtagt tac tta gcc tgg tac caa cag aaa cct ggc cag gct ccc aggctc ctc atc tat gat gca tcc aac agg gcc act ggc atc cca gccagg ttc agt ggc agt ggg tct ggg aca gac ttc act ctc acc atcagc agc cta gag cct gaa gat ttt gca gtt tat tac tgt cag cagagt agc aac tgg cct cgg acg ttc ggc caa ggg acc aag gtg gaa atc aaa 23Heavy Chain CDR1 Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 18 from WO 2006/121168) NSGMH 24Heavy Chain CDR2 Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 25 from WO 2006/121168) VIWYDGSKRYYADSVKG 25Heavy Chain CDR3 Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 32 from WO 2006/121168) NDDY 26Light Chain CDR1 Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 39 from WO 2006/121168) RASQSVSSYLA 27Light Chain CDR2 Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 46 from WO 2006/121168) DASNRAT 28Light Chain CDR3 Amino Acid SequenceAnti-PD-1 mAb (BMS936558; 5C4 in WO 2006/121168)(SEQ ID NO: 53 from WO 2006/121168) QQSSNWPRT 29Complete PD-1 sequence (GenBank Accession No.: U64863)agtttccctt ccgctcacct ccgcctgagc agtggagaag gcggcactctggtggggctg ctccaggcat gcagatccca caggcgccct ggccagtcgtctgggcggtg ctacaactgg gctggcggcc aggatggttc ttagactccccagacaggcc ctggaacccc cccaccttct tcccagccct gctcgtggtgaccgaagggg acaacgccac cttcacctgc agcttctcca acacatcggagagcttcgtg ctaaactggt accgcatgag ccccagcaac cagacggacaagctggccgc cttccccgag gaccgcagcc agcccggcca ggactgccgcttccgtgtca cacaactgcc caacgggcgt gacttccaca tgagcgtggtcagggcccgg cgcaatgaca gcggcaccta cctctgtggg gccatctccctggcccccaa ggcgcagatc aaagagagcc tgcgggcaga gctcagggtgacagagagaa gggcagaagt gcccacagcc caccccagcc cctcacccaggccagccggc cagttccaaa ccctggtggt tggtgtcgtg ggcggcctgctgggcagcct ggtgctgcta gtctgggtcc tggccgtcat ctgctcccgggccgcacgag ggacaatagg agccaggcgc accggccagc ccctgaaggaggacccctca gccgtgcctg tgttctctgt ggactatggg gagctggatttccagtggcg agagaagacc ccggagcccc ccgtgccctg tgtccctgagcagacggagt atgccaccat tgtctttcct agcggaatgg gcacctcatcccccgcccgc aggggctcag ccgacggccc tcggagtgcc cagccactgaggcctgagga tggacactgc tcttggcccc tctgaccggc ttccttggccaccagtgttc tgcagaccct ccaccatgag cccgggtcag cgcatttcctcaggagaagc aggcagggtg caggccattg caggccgtcc aggggctgagctgcctgggg gcgaccgggg ctccagcctg cacctgcacc aggcacagccccaccacagg actcatgtct caatgcccac agtgagccca ggcagcaggtgtcaccgtcc cctacaggga gggccagatg cagtcactgc ttcaggtcctgccagcacag agctgcctgc gtccagctcc ctgaatctct gctgctgctgctgctgctgc tgctgctgcc tgcggcccgg ggctgaaggc gccgtggccctgcctgacgc cccggagcct cctgcctgaa cttgggggct ggttggagatggccttggag cagccaaggt gcccctggca gtggcatccc gaaacgccctggacgcaggg cccaagactg ggcacaggag tgggaggtac atggggctggggactcccca ggagttatct gctccctgca ggcctagaga agtttcagggaaggtcagaa gagctcctgg ctgtggtggg cagggcagga aacccctcccacctttacac atgcccaggc agcacctcag gccctttgtg gggcagggaagctgaggcag taagcgggca ggcagagctg gaggcctttc aggccagccagcactctggc ctcctgccgc cgcattccac cccagcccct cacaccactcgggagaggga catcctacgg tcccaaggtc aggagggcag ggctggggttgactcaggcc cctcccagct gtggccacct gggtgttggg agggcagaagtgcaggcacc tagggccccc catgtgccca ccctgggagc tctccttggaacccattcct gaaattattt aaaggggttg gccgggctcc caccagggcctgggtgggaa ggtacaggcg ttcccccggg gcctagtacc cccgcgtggcctatccactc ctcacatcca cacactgcac ccccactcct ggggcagggccaccagcatc caggcggcca gcaggcacct gagtggctgg gacaagggatcccccttccc tgtggttcta ttatattata attataatta aatatgagag catgctHeavy Chain Nucleotide Sequence Anti-LAG-3 mAb (BMS-986016)caggtgcagctacagcagtggggcgcaggactgttgaagccttcggagaccctgtccctcacctgcgctgtctatggtgggtccttcagtgattactactggaactggatccgccagcccccagggaaggggctggagtggattggggaaatcaatcatcgtggaagcaccaactccaacccgtccctcaagagtcgagtcaccctatcactagacacgtccaagaaccagttctccctgaagctgaggtctgtgaccgccgcggacacggctgtgtattactgtgcgtttggatatagtgactacgagtacaactggttcgacccctggggccagggaaccctggtcaccgtctcctcagctagcaccaagggcccatccgtcttccccctggcgccctgctccaggagcacctccgagagcacagccgccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacgaagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccccatgcccaccatgcccagcacctgagttcctggggggaccatcagtcttcctgttccccccaaaacccaaggacactctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaactggtacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctcccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgcccccatcccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacacagaagagcctctccctgtctctgggtaaatga Light Chain Nucleotide SequenceAnti-LAG-3 mAb (BMS-986016)gaaattgtgttgacacagtctccagccaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtattagcagctacttagcctggtaccaacagaaacctggccaggctcccaggctcctcatctatgatgcatccaacagggccactggcatcccagccaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagcctagagcctgaagattttgcagtttattactgtcagcagcgtagcaactggcctctcacttttggccaggggaccaacctggagatcaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttag

1-20. (canceled)
 21. A kit for treating a solid tumor in a humanpatient, the kit comprising: (a) an 80 mg dose of an anti-LAG-3 antibodycomprising CDR1, CDR2 and CDR3 domains of the heavy chain variableregion having the sequence set forth in SEQ ID NO:3, and CDR1, CDR2 andCDR3 domains of the light chain variable region having the sequence setforth in SEQ ID NO:5; (b) a 240 mg dose of an anti-PD-1 antibodycomprising CDR1, CDR2 and CDR3 domains of the heavy chain variableregion having the sequence set forth in SEQ ID NO: 19, and CDR1, CDR2and CDR3 domains of the light chain variable region having the sequenceset forth in SEQ ID NO:21; and (c) instructions for using the anti-LAG-3antibody and anti-PD-1 antibody in a method for treating a solid tumor.22. (canceled)
 23. (canceled)
 24. The kit of claim 21, wherein theanti-PD-1 and anti-LAG-3 antibodies are formulated for intravenousadministration.
 25. The kit of claim 21, wherein the anti-PD-1 andanti-LAG-3 antibodies are formulated together.
 26. The kit of claim 21,wherein the anti-PD-1 and anti-LAG-3 antibodies are formulatedseparately.
 27. The kit of claim 21, wherein the solid tumor is chosenfrom melanoma, non-small cell lung cancer (NSCLC), human papilloma virus(HPV)-related tumor, and gastric adenocarcinoma.
 28. The kit of claim21, wherein the anti-LAG-3 antibody comprises (a) a heavy chain variableregion CDR1 comprising the sequence set forth in SEQ ID NO:7; (b) aheavy chain variable region CDR2 comprising the sequence set forth inSEQ ID NO:8; (c) a heavy chain variable region CDR3 comprising thesequence set forth in SEQ ID NO:9; (d) a light chain variable regionCDR1 comprising the sequence set forth in SEQ ID NO:10; (e) a lightchain variable region CDR2 comprising the sequence set forth in SEQ IDNO:11; and (f) a light chain variable region CDR3 comprising thesequence set forth in SEQ ID NO:12.
 29. The kit of claim 21, wherein theanti-LAG-3 antibody comprises heavy and light chain variable regionscomprising the sequences set forth in SEQ ID NOs:3 and 5, respectively.30. The kit of claim 21, wherein the anti-LAG-3 antibody comprises heavyand light chains comprising the sequences set forth in SEQ ID NOs: 1 and2, respectively.
 31. The kit of claim 21, wherein the anti-PD-1 antibodycomprises (a) a heavy chain variable region CDR1 comprising the sequenceset forth in SEQ ID NO:23; (b) a heavy chain variable region CDR2comprising the sequence set forth in SEQ ID NO:24; (c) a heavy chainvariable region CDR3 comprising the sequence set forth in SEQ ID NO:25;(d) a light chain variable region CDR1 comprising the sequence set forthin SEQ ID NO:26; (e) a light chain variable region CDR2 comprising thesequence set forth in SEQ ID NO:27; and (f) a light chain variableregion CDR3 comprising the sequence set forth in SEQ ID NO:28.
 32. Thekit of claim 21, wherein the anti-PD-1 antibody comprises heavy andlight chain variable regions comprising the sequences set forth in SEQID NOs: 19 and 21, respectively.
 33. The kit of claim 21, wherein theanti-PD-1 antibody comprises heavy and light chains comprising thesequences as set forth in SEQ ID NOs: 17 and 18, respectively.
 34. Thekit of claim 21, wherein the anti-LAG-3 antibody and/or anti-PD-1antibody is a full-length antibody.
 35. The kit of claim 21, wherein theanti-LAG-3 antibody has a S228P mutation
 36. The kit of claim 21,wherein the patient has been previously treated with anti-PD-1 oranti-PD-L1 antibody therapy.
 37. The kit of claim 21, further comprisinga dose of an anti-CTLA-4 antibody.
 38. The kit of claim 37, wherein theanti-CTLA-4 antibody is ipilimumab.